Jason H Karnes

Interests

Research

Cardiovascular PharmacogenomicsImmunology and PharmacogenomicsClinical Implementation of Pharmacogenomics

Teaching

Clinical training in pharmacogenomicsGraduate student research developmentBiostatistics

Courses

Scholarly Contributions

Chapters

• Karnes, J. H., & Ramsey, L. (2021). Pharmacogenetics and Molecular Testing. In 7th edition of Basic Skills in Interpreting Laboratory Data. American Society of Health-System Pharmacists.
• Pavlos, R., Karnes, J. H., Trubiano, J., Peter, J., & Phillips, E. (2018). Pharmacogenomics of Drug Allergy. In Drug Allergy Testing, 1st Edition(pp 39-51). St Louis, Missouri: Elsevier.
• Pavlos, R., Karnes, J., Trubiano, J., Peter, J., & Phillips, E. (2017). Pharmacogenomics of Drug Allergy. In Drug Allergy Testing, 1st Edition. doi:10.1016/B978-0-323-48551-7.00005-5
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  Adverse drug reactions (ADRs) are associated with significant morbidity, mortality, and cost. The pharmacogenomics of ADRs may encompass “on-target” pharmacologically mediated reactions or “off-target” pharmacologic or immune-mediated ADRs. Immune-mediated ADRs may be associated with immunologic memory of varying duration or without immune memory yet exhibit an immunologic phenotype such as urticaria. On-target pharmacologic ADRs are those that typically develop in a concentration-dependent manner and therefore involve genes associated with drug disposition and/or a known pharmacodynamic target. Reactions with an off-target pharmacologic or immunologic component involve genes associated with diverse pharmacologic, innate, and adaptive immune system pathways. These reactions include non-IgE-mediated mast cell activation, aspirin-exacerbated respiratory disease, nonimmune drug-induced thrombocytopenia, and heparin-induced thrombocytopenia, and also those ADRs with known immunologic memory such as IgE-mediated reactions and T cell-mediated delayed drug reactions. The utility of pharmacogenomic screening is influenced by a variety of economic, genetic, and clinical factors, which determine the overall burden of a particular ADR. Regardless of whether genes associated with drug allergy syndromes translate directly into the clinic as preventive markers, they provide valuable insights into mechanisms and pathogenesis that may help identify future therapeutic targets and guide safer drug design and development. This chapter discusses specific examples of each ADR classification and the associated pharmacogenomic risk factors and will highlight examples where pharmacogenomic associations have been successfully implemented into personalized medicine programs, as well as opportunities for future translation.

Journals/Publications

• Baskir, R., Lee, M., McMaster, S. J., Lee, J., Blackburne-Proctor, F., Azuine, R., Mack, N., Schully, S. D., Mendoza, M., Sanchez, J., Crosby, Y., Zumba, E., Hahn, M., Aspaas, N., Elmi, A., Alerté, S., Stewart, E., Wilfong, D., Doherty, M., , Farrell, M. M., et al. (2025). Research for all: building a diverse researcher community for the All of Us Research Program. Journal of the American Medical Informatics Association : JAMIA, 32(1), 38-50.
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  The NIH All of Us Research Program (All of Us) is engaging a diverse community of more than 10 000 registered researchers using a robust engagement ecosystem model. We describe strategies used to build an ecosystem that attracts and supports a diverse and inclusive researcher community to use the All of Us dataset and provide metrics on All of Us researcher usage growth.
• Giles, J. B., Martinez, K. L., Steiner, H. E., Klein, A., Ooi, A., Pryor, J., Sweitzer, N., Fuchs, D., & Karnes, J. H. (2024). Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia. Cardiovascular toxicology, 24(9), 968-981.
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  Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts.
• Giles, J. B., Martinez, K. L., Steiner, H. E., Klein, A., Ooi, A., Pryor, J., Sweitzer, N., Fuchs, D., & Karnes, J. H. (2024). Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia. Research square.
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  Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD] of 0.93 (SD = 1.21) units and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody negative patients. We observed statistical differences between antibody positive and negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including binding studies and larger observational cohorts.
• Haddad, A., Radhakrishnan, A., McGee, S., Smith, J. D., Karnes, J. H., Venner, E., Wheeler, M. M., Patterson, K., Walker, K., Kalra, D., Kalla, S. E., Wang, Q., Gibbs, R. A., Jarvik, G. P., Sanchez, J., Musick, A., Ramirez, A. H., Denny, J. C., & Empey, P. E. (2024). Frequency of pharmacogenomic variation and medication exposures among All of Us Participants. medRxiv : the preprint server for health sciences.
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  Pharmacogenomics promises improved outcomes through individualized prescribing. However, the lack of diversity in studies impedes clinical translation and equitable application of precision medicine. We evaluated the frequencies of PGx variants, predicted phenotypes, and medication exposures using whole genome sequencing and EHR data from nearly 100k diverse All of Us Research Program participants. We report 100% of participants carried at least one pharmacogenomics variant and nearly all (99.13%) had a predicted phenotype with prescribing recommendations. Clinical impact was high with over 20% having both an actionable phenotype and a prior exposure to an impacted medication with pharmacogenomic prescribing guidance. Importantly, we also report hundreds of alleles and predicted phenotypes that deviate from known frequencies and/or were previously unreported, including within admixed American and African ancestry groups.
• Jafari, E., Blackman, M. H., Karnes, J. H., Van Driest, S. L., Crawford, D. C., Choi, L., & McDonough, C. W. (2024). Using electronic health records for clinical pharmacology research: Challenges and considerations. Clinical and translational science, 17(7), e13871.
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  Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions. This is largely due to challenges specific to deriving drug-related phenotypes from the EHR. There is great potential for EHR-based discovery in clinical pharmacology research, and there is a critical need to address specific challenges related to accurate and reproducible derivation of drug-related phenotypes from the EHR. This review provides a detailed evaluation of challenges and considerations for deriving drug-related data from EHRs. We provide an examination of EHR-based computable phenotypes and discuss cutting-edge approaches to map medication information for clinical pharmacology research, including medication-based computable phenotypes and natural language processing. We also discuss additional considerations such as data structure, heterogeneity and missing data, rare phenotypes, and diversity within the EHR. By further understanding the complexities associated with conducting clinical pharmacology research using EHR-based data, investigators will be better equipped to design thoughtful studies with more reproducible results. Progress in utilizing EHRs for clinical pharmacology research should lead to significant advances in our ability to understand differential drug response and predict adverse drug reactions.
• Khajouei, E., Ghisays, V., Piras, I. S., Martinez, K. L., Naymik, M., Ngo, P., Tran, T. C., Denny, J. C., Wheeler, T. J., Huentelman, M. J., Reiman, E. M., & Karnes, J. H. (2024). Phenome-Wide Association of Alleles in the Research Program. medRxiv : the preprint server for health sciences.
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  Genetic variation in is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease risk. However, prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. We utilized a phenome-wide association study (PheWAS) approach to explore -associated phenotypes in the Research Program.
• Martinez, K. L., Klein, A., Martin, J. R., Sampson, C. U., Giles, J. B., Beck, M. L., Bhakta, K., Quatraro, G., Farol, J., & Karnes, J. H. (2024). Disparities in ABO blood type determination across diverse ancestries: a systematic review and validation in the All of Us Research Program. Journal of the American Medical Informatics Association : JAMIA.
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  ABO blood types have widespread clinical use and robust associations with disease. The purpose of this study is to evaluate the portability and suitability of tag single-nucleotide polymorphisms (tSNPs) used to determine ABO alleles and blood types across diverse populations in published literature.
• Singh, S., Stocco, G., Theken, K. N., Dickson, A., Feng, Q., Karnes, J. H., Mosley, J. D., & El Rouby, N. (2024). Pharmacogenomics polygenic risk score: Ready or not for prime time?. Clinical and translational science, 17(8), e13893.
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  Pharmacogenomic Polygenic Risk Scores (PRS) have emerged as a tool to address the polygenic nature of pharmacogenetic phenotypes, increasing the potential to predict drug response. Most pharmacogenomic PRS have been extrapolated from disease-associated variants identified by genome wide association studies (GWAS), although some have begun to utilize genetic variants from pharmacogenomic GWAS. As pharmacogenomic PRS hold the promise of enabling precision medicine, including stratified treatment approaches, it is important to assess the opportunities and challenges presented by the current data. This assessment will help determine how pharmacogenomic PRS can be advanced and transitioned into clinical use. In this review, we present a summary of recent evidence, evaluate the current status, and identify several challenges that have impeded the progress of pharmacogenomic PRS. These challenges include the reliance on extrapolations from disease genetics and limitations inherent to pharmacogenomics research such as low sample sizes, phenotyping inconsistencies, among others. We finally propose recommendations to overcome the challenges and facilitate the clinical implementation. These recommendations include standardizing methodologies for phenotyping, enhancing collaborative efforts, developing new statistical methods to capitalize on drug-specific genetic associations for PRS construction. Additional recommendations include enhancing the infrastructure that can integrate genomic data with clinical predictors, along with implementing user-friendly clinical decision tools, and patient education. Ethical and regulatory considerations should address issues related to patient privacy, informed consent and safe use of PRS. Despite these challenges, ongoing research and large-scale collaboration is likely to advance the field and realize the potential of pharmacogenomic PRS.
• Tai, Y. Y., Yu, Q., Tang, Y., Sun, W., Kelly, N. J., Okawa, S., Zhao, J., Schwantes-An, T. H., Lacoux, C., Torrino, S., Al Aaraj, Y., El Khoury, W., Negi, V., Liu, M., Corey, C. G., Belmonte, F., Vargas, S. O., Schwartz, B., Bhat, B., , Chau, B. N., et al. (2024). Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension. Science translational medicine, 16(729), eadd2029.
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  Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine -methyltransferase 2E-antisense 1 () and histone lysine N-methyltransferase 2E (). stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the /KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.
• Tang, H., Gupta, A., Morrisroe, S. A., Bao, C., Schwantes-An, T. H., Gupta, G., Liang, S., Sun, Y., Chu, A., Luo, A., Ramamoorthi Elangovan, V., Sangam, S., Shi, Y., Naidu, S. R., Jheng, J. R., Ciftci-Yilmaz, S., Warfel, N. A., Hecker, L., Mitra, S., , Coleman, A. W., et al. (2024). Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension. Circulation.
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  The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1.
• Venner, E., Patterson, K., Kalra, D., Wheeler, M. M., Chen, Y. J., Kalla, S. E., Yuan, B., Karnes, J. H., Walker, K., Smith, J. D., McGee, S., Radhakrishnan, A., Haddad, A., Empey, P. E., Wang, Q., Lichtenstein, L., Toledo, D., Jarvik, G., Musick, A., , Gibbs, R. A., et al. (2024). Author Correction: The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities. Communications biology, 7(1), 713.
• Casanova, N. G., Camp, S. M., Gonzalez-Garay, M. L., Batai, K., Garman, L., Montgomery, C. G., Ellis, N., Kittles, R., Bime, C., Hsu, A. P., Holland, S., Lussier, Y. A., Karnes, J., Sweiss, N., Maier, L. A., Koth, L., Moller, D. R., Kaminski, N., & Garcia, J. G. (2023). Examination of eQTL Polymorphisms Associated with Increased Risk of Progressive Complicated Sarcoidosis in European and African Descent Subjects. European journal of respiratory medicine, 5(1), 359-371.
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  A limited pool of SNPs are linked to the development and severity of sarcoidosis, a systemic granulomatous inflammatory disease. By integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) single nuclear polymorphisms (SNPs), we aimed to identify novel sarcoidosis SNPs potentially influencing the development of complicated sarcoidosis.
• Feng, J., Symonds, E. A., & Karnes, J. H. (2023). Visualization and Quantification of the Association Between Breast Cancer and Cholesterol in the All of Us Research Program. Cancer informatics, 22, 11769351221144132.
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  Epidemiologic evidence for the association of cholesterol and breast cancer is inconsistent. Several factors may contribute to this inconsistency, including limited sample sizes, confounding effects of antihyperlipidemic treatment, age, and body mass index, and the assumption that the association follows a simple linear function. Here, we aimed to address these factors by combining visualization and quantification a large-scale contemporary electronic health record database (the All of Us Research Program). We find clear visual and quantitative evidence that breast cancer is strongly, positively, and near-linearly associated with total cholesterol and low-density lipoprotein cholesterol, but not associated with triglycerides. The association of breast cancer with high-density lipoprotein cholesterol was non-linear and age dependent. Standardized odds ratios were 2.12 (95% confidence interval 1.9-2.48),  = 5.6 × 10 for total cholesterol; 1.99 (1.75-2.26),  = 2.6 × 10 for low-density lipoprotein cholesterol; 1.69 (1.3-2.2),  = 9.0 × 10 for high-density lipoprotein cholesterol at age 
• Giles, J. B., Rollin, J., Martinez, K. L., Selleng, K., Thiele, T., Pouplard, C., Sheppard, J. I., Heddle, N. M., Phillips, E. J., Roden, D. M., Gruel, Y., Warkentin, T. E., Greinacher, A., & Karnes, J. H. (2023). Laboratory and demographic predictors of functional assay positive status in suspected heparin-induced thrombocytopenia: A multicenter retrospective cohort study. Thrombosis research, 229, 198-208.
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  Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against platelet factor 4 (PF4) bound to heparin anticoagulants. A priori identification of patients at-risk for HIT remains elusive and a number of risk factors have been identified, but these associations and their effect sizes have limited validation in large cohorts of suspected HIT patients. The aim of this study was to investigate existing anti-PF4/heparin antibody thresholds and model the relationship of demographic variables and anti-PF4/heparin antibody levels with functional assay positivity across multiple institutions in the absence of detailed clinical data. In a large collection of suspected HIT patients (n = 8904), we tested for associations between laboratory and demographic variables and functional assay positive status as well as anti-PF4/heparin antibody levels. We also tested for correlation between IgG-specific and polyspecific (IgG/IgA/IgM) anti-PF4/heparin antibody values and their ability to predict functional assay positive status using area under the receiver operating characteristic (AUROC). Logistic regression identified increasing anti-PF4/heparin antibody OD levels (OR = 51.84 [37.27-74.34], p 
• Lynn, H., Sun, X., Casanova, N. G., Bime, C., Reyes Hernon, V., Lanham, C., Oita, R. C., Ramos, N., Sun, B., Coletta, D. K., Camp, S. M., Karnes, J. H., Ellis, N. A., & Garcia, J. G. (2023). Linkage of NAMPT promoter variants to eNAMPT secretion, plasma eNAMPT levels, and ARDS severity. Therapeutic advances in respiratory disease, 17, 17534666231181262.
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  eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel DAMP and TLR4 ligand, is a druggable ARDS therapeutic target with promoter SNPs associated with ARDS severity. This study assesses the previously unknown influence of promoter SNPs on transcription, eNAMPT secretion, and ARDS severity.
• Miller, E., Sampson, C. U., Desai, A. A., & Karnes, J. H. (2023). Differential drug response in pulmonary arterial hypertension: The potential for precision medicine. Pulmonary circulation, 13(4), e12304.
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  Pulmonary arterial hypertension (PAH) is a rare, complex, and deadly cardiopulmonary disease. It is characterized by changes in endothelial cell function and smooth muscle cell proliferation in the pulmonary arteries, causing persistent vasoconstriction, resulting in right heart hypertrophy and failure. There are multiple drug classes specific to PAH treatment, but variation between patients may impact treatment response. A small subset of patients is responsive to pulmonary vasodilators and can be treated with calcium channel blockers, which would be deleterious if prescribed to a typical PAH patient. Little is known about the underlying cause of this important difference in vasoresponsive PAH patients. Sex, race/ethnicity, and pharmacogenomics may also factor into efficacy and safety of PAH-specific drugs. Research has indicated that endothelin receptor antagonists may be more effective in women and there have been some minor differences found in certain races and ethnicities, but these findings are muddled by the impact of socioeconomic factors and a lack of representation of non-White patients in clinical trials. Genetic variants in genes such as , , , , , , and may influence the efficacy and safety of certain PAH-specific drugs. PAH research faces many challenges, but there is potential for new methodologies to glean new insights into PAH development and treatment.
• Sangam, S., Sun, X., Schwantes-An, T. H., Yegambaram, M., Lu, Q., Shi, Y., Cook, T., Fisher, A., Frump, A. L., Coleman, A., Sun, Y., Liang, S., Crawford, H., Lutz, K. A., Maun, A. D., Pauciulo, M. W., Karnes, J. H., Chaudhary, K. R., Stewart, D. J., , Langlais, P. R., et al. (2023). SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics. American journal of respiratory and critical care medicine, 207(8), 1055-1069.
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  Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2- () deletion and attenuated by transgenic Tie2- overexpression (). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of and reduced in those from mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of promoter activity, mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a risk variant, rs10103692, and reduced plasma citrate concentrations ( = 1,326). Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and genetics in PAH.
• Steiner, H., Carrion, K., Giles, J., Lima, A., Yee, K., Sun, X., Cavallari, L., Perera, M., Duconge, J., & Karnes, J. (2023). Local Ancestry-Informed Candidate Pathway Analysis of Warfarin Stable Dose in Latino Populations. Clinical Pharmacology and Therapeutics, 113(3). doi:10.1002/cpt.2787
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  Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of five variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (P < 0.0125) in standard models. Local ancestry-adjusted analysis unveiled 35 associated variants with absolute effects ranging from β = 9.04 (±2.23) to 39.18 (±10.89) per ancestral allele in the discovery cohort and β = 6.47 (± 2.02) to 17.82 (± 6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.
• Chen, Y., Gibbs, R. A., Haddad, A., Jarvik, G., Kalla, S. E., Kalra, D., Karnes, J. H., Lee, B., Mcgee, S., Musick, A., Patterson, K., Radhakrishnan, A., Smith, J. D., Toledo, D., Venner, E., Walker, K., Wang, Q., Wheeler, M. M., & Yuan, B. (2022). The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities. medRxiv (Cold Spring Harbor Laboratory). doi:10.1101/2022.12.19.22283658
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  Abstract Disparities in the data that underlies clinical genomic interpretation is an acknowledged problem but there is a paucity of data demonstrating it. The National Institutes of Health’s All of Us Research Program aims to collect whole genome sequences, electronic health record (EHR) data, surveys and physical measurements for over a million participants of diverse ancestry and varied access to healthcare resources. We grouped participants by computed genetic ancestry and summarized the frequency of pathogenic variation within these groups. The European subgroup showed the highest rate of pathogenic variation (2.1%), with other ancestry groups ranging from 1.04% (East Asian) to 1.87% (‘Other’). Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer, Hypercholesterolemia or Hemochromatosis. Variant frequencies were consistent with gnomAD and some notable exceptions were resolved using gnomAD subsets. We additionally use this data to enrich sets of participants for specific genetic findings and to calculate penetrance. Differences in the frequency of pathogenic variants observed between ancestral groups generally indicate biases of ascertainment, but some may indicate differences in disease prevalence. These analyses are available on the All of Us Researcher Workbench.
• Giles, J. B., Steiner, H. E., Rollin, J., Shaffer, C. M., Momozawa, Y., Mushiroda, T., Inai, C., Selleng, K., Thiele, T., Pouplard, C., Heddle, N. M., Kubo, M., Miller, E. C., Martinez, K. L., Phillips, E. J., Warkentin, T. E., Gruel, Y., Greinacher, A., Roden, D. M., & Karnes, J. H. (2022). Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia. Blood advances, 6(14), 4137-4146.
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  Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10-8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10-4). The top variant in both cohorts was rs1555175145 (discovery β = -0.112 [0.018], P = 2.50 × 10-5; replication β = -0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: "Leukocyte Transendothelial Migration," "Innate Immune Response," and "Lyase Activity." Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.
• Harbaum, L., Rhodes, C. J., Wharton, J., Lawrie, A., Karnes, J. H., Desai, A. A., Nichols, W. C., Humbert, M., Montani, D., Girerd, B., Sitbon, O., Boehm, M., Novoyatleva, T., Schermuly, R. T., Ghofrani, H. A., Toshner, M., Kiely, D. G., Howard, L. S., Swietlik, E. M., , Gräf, S., et al. (2022). Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine, 205(12), 1449-1460.
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  Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on -pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.
• Karnes, J. H., Rollin, J., Giles, J. B., Martinez, K. L., Steiner, H. E., Shaffer, C. M., Momozawa, Y., Inai, C., Bombin, A., Shi, M., Mosley, J. D., Stanaway, I., Selleng, K., Thiele, T., Mushiroda, T., Pouplard, C., Heddle, N. M., Kubo, M., Phillips, E. J., , Warkentin, T. E., et al. (2022). ABO O blood group as a risk factor for platelet reactivity in heparin-induced thrombocytopenia. Blood, 140(3), 274-284.
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  Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10-8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10-209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10-9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.
• Karnes, J., Asempa, T., Barreto, J., Belcher, R., Bissell, B., Gammal, R., Kier, K., Lee, C., Liu, L., McCune, J., Minhaj, F., Newsome, A., Ning, J., & Bookstaver, P. (2022). The essential research curriculum for doctor of pharmacy degree programs – 2021. JACCP Journal of the American College of Clinical Pharmacy, 5(3). doi:10.1002/jac5.1603
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  Training in the scientific method and research design in doctor of pharmacy (Pharm.D.) curricula enables critical thinking, acquisition of reliable information, rigorous evaluation of emerging literature, and application of evidence-based medicine in practice. Although research skills are essential for clinical pharmacists and many professional societies recognize the critical need for research in the Pharm.D. curriculum, standardization regarding essential research curricular competencies and content is lacking. Consequently, research skill development is often de-emphasized in pharmacy education in favor of clinical knowledge and skills. This update to the recommendations of the American College of Clinical Pharmacy's 2008-2009 Task Force on Research in the Professional Curriculum is provided to meet the evolving needs of contemporary pharmacy practice. The update discusses the importance of research training for Pharm.D. students, proposes essential research competencies and curriculum content for Pharm.D. programs, and highlights several successful strategies for fostering research among Pharm.D. students. In particular, the update advocates enhanced adoption of minimum standards for research skill development across Pharm.D. programs and integration of advanced research competencies to support the development of Pharm.D.-trained scientists.
• Miller, E., Norwood, C., Giles, J. B., Huddart, R., Karnes, J. H., Whirl-Carrillo, M., & Klein, T. E. (2022). PharmGKB summary: heparin-induced thrombocytopenia pathway, adverse drug reaction. Pharmacogenetics and genomics, 32(3), 117-124.
• Steiner, H. E., Carrion, K. C., Giles, J. B., Lima, A. R., Yee, K., Sun, X., Cavallari, L. H., Perera, M. A., Duconge, J., & Karnes, J. H. (2022). Local Ancestry-Informed Candidate Pathway Analysis of Warfarin Stable Dose in Latino Populations. Clinical pharmacology and therapeutics.
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  Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of five variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (P 
• Steiner, H. E., Gee, K., Giles, J., Knight, H., Hurwitz, B. L., & Karnes, J. H. (2022). Role of the gut microbiome in cardiovascular drug response: The potential for clinical application. Pharmacotherapy, 42(2), 165-176.
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  Response to cardiovascular drugs can vary greatly between individuals, and the role of the microbiome in this variability is being increasingly appreciated. Recent evidence indicates that bacteria and other microbes are responsible for direct and indirect effects on drug efficacy and toxicity. Pharmacomicrobiomics aims to uncover variability in drug response due to microbes in the human body, which may alter drug disposition through microbial metabolism, interference by microbial metabolites, or modification of host enzymes. In this review, we present recent advances in our understanding of the interplay between microbes, host metabolism, and cardiovascular drugs. We report numerous cardiovascular drugs with evidence of, or potential for, gut-microbe interactions. However, the effects of gut microbiota on many cardiovascular drugs are yet uninvestigated. Finally, we consider potential clinical applications for the described findings.
• Steiner, H. E., Patterson, H. K., Giles, J. B., & Karnes, J. H. (2022). Bringing pharmacomicrobiomics to the clinic through well-designed studies. Clinical and translational science, 15(10), 2303-2315.
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  Pharmacomicrobiomic studies investigate drug-microbiome interactions, such as the effect of microbial variation on drug response and disposition. Studying and understanding the interactions between the gut microbiome and drugs is becoming increasingly relevant to clinical practice due to its potential for avoiding adverse drug reactions or predicting variability in drug response. The highly variable nature of the human microbiome presents significant challenges to assessing microbes' influence. Studies aiming to explore drug-microbiome interactions should be well-designed to account for variation in the microbiome over time and collect data on confounders such as diet, disease, concomitant drugs, and other environmental factors. Here, we assemble a set of important considerations and recommendations for the methodological features required for performing a pharmacomicrobiomic study in humans with a focus on the gut microbiome. Consideration of these factors enable discovery, reproducibility, and more accurate characterization of the relationships between a given drug and the microbiome. Furthermore, appropriate interpretation and dissemination of results from well-designed studies will push the field closer to clinical relevance and implementation.
• Toshner, M., Church, C., Harbaum, L., Rhodes, C., Villar Moreschi, S., Liley, J., Jones, R., Arora, A., Batai, K., Desai, A., Coghlan, J., Gibbs, S., Gor, D., Harlow, L., Hernandez-Sanchez, J., Howard, L., Humbert, M., Karnes, J., Kiely, D., , Kittles, R., et al. (2022). Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. European Respiratory Journal, 59(3). doi:10.1183/13993003.02463-2020
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  Background Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. Methods We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11744 individuals with European ancestry including 2085 patients with idiopathic/ heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. Results We recruited 29 patients (male/female 10/19; mean±SD age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). Conclusion Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
• Abraham, I., Alkhatib, N. S., Erstad, B. L., Gharaibeh, M., Karnes, J. H., Klimecki, W. T., Lee, C. S., Ramos, K. S., Slack, M. K., & Sweitzer, N. K. (2021). Ex Ante Economic Evaluation of Arg389 Genetically Targeted Treatment with Bucindolol versus Empirical Treatment with Carvedilol in NYHA III/IV Heart Failure.. American Journal of Cardiovascular Drugs, 21(2), 205-217. doi:10.1007/s40256-020-00425-x
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  The Beta-Blocker Evaluation Survival Trial showed no survival benefit for bucindolol in New York Heart Association (NYHA) class III/IV heart failure (HF) with reduced ejection fraction, but subanalyses suggested survival benefits for non-Black subjects and Arg389 homozygotes. We conducted an ex ante economic evaluation of Arg389 targeted treatment with bucindolol versus carvidolol, complementing a previous ex ante economic evaluation of bucindolol preceded by genetic testing for the Arg389 polymorphism, in which genetic testing prevailed economically over no testing. A decision tree analysis with an 18-month time horizon was performed to estimate the cost effectiveness/cost utility of trajectories of 100%, 50%, and 0% of patients genetically tested for Arg389 and comparing bucindolol with empirical carvedilol treatment as per prior BEST subanalyses. Incremental cost-effectiveness/cost-utility ratios (ICERs/ICURs) were estimated. Race-based analyses for non-White subjects at 100% testing showed a loss of (0.04) life-years and (0.03) quality-adjusted life-years (QALYs) at an incremental cost of $2185, yielding a negative ICER of ($54,625)/life-year and ICUR of ($72,833)/QALY lost; at 50%, the analyses showed a loss of (0.27) life-years and (0.16) QALYs at an incremental cost of $1843, yielding a negative ICER of ($6826)/life-year and ICUR of ($11,519)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. Arg389 homozygote analyses at 100% testing showed incremental gains of 0.02 life-years and 0.02 QALYs at an incremental cost of $378, yielding an ICER of 18,900/life-year and ICUR of $18,900/QALY gained; at 50%, the analyses showed a loss of (0.24) life-years and (0.09) QALYs at an incremental cost of $1039, yielding a negative ICER of ($4329)/life-year and ICUR of ($9336)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. This independent ex ante economic evaluation suggests that genetically targeted treatment with bucindolol is unlikely to yield clinicoeconomic benefits over empirical treatment with carvedilol in NYHA III/IV HF.
• Callaghan, J. T., Caudle, K. E., Fohner, A. E., Formea, C. M., Gaedigk, A., Huddart, R., Karnes, J. H., Klein, T. E., Lee, M. T., Llerena, A., Mintzer, S., Phillips, E. J., Rettie, A. E., Somogyi, A. A., Whirl-carrillo, M., Callaghan, J. T., Caudle, K. E., Fohner, A. E., Formea, C. M., , Gaedigk, A., et al. (2021). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update.. Clinical pharmacology and therapeutics, 109(2), 302-309. doi:10.1002/cpt.2008
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  Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).
• Clark, C. R., Chandler, P. D., Zhou, G., Noel, N., Achilike, C., Mendez, L., O'Connor, G. T., Smoller, J. W., Weiss, S. T., Murphy, S. N., Ommerborn, M. J., Karnes, J. H., Klimentidis, Y. C., Jordan, C. D., Hiatt, R. A., Ramirez, A. H., Loperena, R., Mayo, K., Cohn, E., , Ohno-Machado, L., et al. (2021). Geographic Variation in Obesity at the State Level in the All of Us Research Program. Preventing chronic disease, 18, E104.
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  National obesity prevention strategies may benefit from precision health approaches involving diverse participants in population health studies. We used cohort data from the National Institutes of Health All of Us Research Program (All of Us) Researcher Workbench to estimate population-level obesity prevalence.
• Cronin, R. M., Halvorson, A. E., Springer, C., Feng, X., Sulieman, L., Loperena-Cortes, R., Mayo, K., Carroll, R. J., Chen, Q., Ahmedani, B. K., Karnes, J., Korf, B., O'Donnell, C. J., Qian, J., & Ramirez, A. H. (2021). Comparison of family health history in surveys vs electronic health record data mapped to the observational medical outcomes partnership data model in the All of Us Research Program. Journal of the American Medical Informatics Association : JAMIA, 28(4), 695-703.
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  Family health history is important to clinical care and precision medicine. Prior studies show gaps in data collected from patient surveys and electronic health records (EHRs). The All of Us Research Program collects family history from participants via surveys and EHRs. This Demonstration Project aims to evaluate availability of family health history information within the publicly available data from All of Us and to characterize the data from both sources.
• Desai, A. A., Karnes, J. H., Kittles, R. A., & Schwantes-an, T. (2021). Reply to Non and Chang: Challenging the Role of Genetic Ancestry in Explaining Racial/Ethnic Health Disparities.. American journal of respiratory and critical care medicine, 203(3), 398-399. doi:10.1164/rccm.202010-3846le
• Deshpande, P., Hertzman, R. J., Palubinsky, A. M., Giles, J. B., Karnes, J. H., Gibson, A., & Phillips, E. J. (2021). Immunopharmacogenomics: Mechanisms of HLA-Associated Drug Reactions. Clinical pharmacology and therapeutics, 110(3), 607-615.
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  The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell-mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug-induced T-cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T-cell-mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA-associated drug reactions and the implications for future translation into clinical care.
• El Rouby, N., Rodrigues Marcatto, L., Claudio, K., Camargo Tavares, L., Steiner, H., Botton, M., Lubitz, S., Fallon, E., Yee, K., Kaye, J., Scott, S., Karnes, J., Caleb Junior de Lima Santos, P., Duconge, J., & Cavallari, L. (2021). Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos. Clinical and Translational Science, 14(1). doi:10.1111/cts.12854
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  We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = −0.29, P < 2.0 × 10−16; β = −0.21, P = 4.7 × 10−7, respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10−4; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = −0.14, P = 2.0 × 10−16), CYP2C9 (β = −0.07, P = 5.6 × 10−10), and CYP4F2 (β = 0.03, P = 3 × 10−3), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43–46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.
• Gee, K., Giles, J., Hurwitz, B. L., Karnes, J. H., Knight, H., & Steiner, H. E. (2021). Role of the gut microbiome in cardiovascular drug response: The potential for clinical application. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 42(2), 165-176. doi:10.1002/phar.2650
• Giacomini, K. M., Karnes, J. H., Crews, K. R., Monte, A. A., Murphy, W. A., Oni-Orisan, A., Ramsey, L. B., Yang, J. J., & Whirl-Carrillo, M. (2021). Advancing Precision Medicine Through the New Pharmacogenomics Global Research Network. Clinical pharmacology and therapeutics, 110(3), 559-562.
• Giles, J. B., Miller, E. C., Steiner, H. E., & Karnes, J. H. (2021). Elucidation of Cellular Contributions to Heparin-Induced Thrombocytopenia Using Omic Approaches. Frontiers in pharmacology, 12, 812830.
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  Heparin-induced thrombocytopenia (HIT) is an unpredictable, complex, immune-mediated adverse drug reaction associated with a high mortality. Despite decades of research into HIT, fundamental knowledge gaps persist regarding HIT likely due to the complex and unusual nature of the HIT immune response. Such knowledge gaps include the identity of a HIT immunogen, the intrinsic roles of various cell types and their interactions, and the molecular basis that distinguishes pathogenic and non-pathogenic PF4/heparin antibodies. While a key feature of HIT, thrombocytopenia, implicates platelets as a seminal cell fragment in HIT pathogenesis, strong evidence exists for critical roles of multiple cell types. The rise in omic technologies over the last decade has resulted in a number of agnostic, whole system approaches for biological research that may be especially informative for complex phenotypes. Applying multi-omics techniques to HIT has the potential to bring new insights into HIT pathophysiology and identify biomarkers with clinical utility. In this review, we review the clinical, immunological, and molecular features of HIT with emphasis on key cell types and their roles. We then address the applicability of several omic techniques underutilized in HIT, which have the potential to fill knowledge gaps related to HIT biology.
• Grace, C., Larriva, M. M., Steiner, H. E., Marupuru, S., Campbell, P. J., Patterson, H., Cropp, C. D., Quinn, D., Klimecki, W., Nix, D. E., Warholak, T., & Karnes, J. H. (2021). Efficacy of personal pharmacogenomic testing as an educational tool in the pharmacy curriculum: A nonblinded, randomized controlled trial. Clinical and translational science, 14(6), 2532-2543.
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  Personal genomic educational testing (PGET) has been suggested as a strategy to improve student learning for pharmacogenomics (PGx), but no randomized studies have evaluated PGET's educational benefit. We investigated the effect of PGET on student knowledge, comfort, and attitudes related to PGx in a nonblinded, randomized controlled trial. Consenting participants were randomized to receive PGET or no PGET (NPGET) during 4 subsequent years of a PGx course. All participants completed a pre-survey and post-survey designed to assess (1) PGx knowledge, (2) comfort with PGx patient education and clinical skills, and (3) attitudes toward PGx. Instructors were blinded to PGET assignment. The Wilcoxon Rank Sum test was used to compare pre-survey and post-survey PGx knowledge, comfort, and attitudes. No differences in baseline characteristics were observed between PGET (n = 117) and NPGET (n = 116) participants. Among all participants, significant improvement was observed in PGx knowledge (mean 57% vs. 39% correct responses; p 
• Hertz, D. L., Arwood, M. J., Stocco, G., Singh, S., Karnes, J. H., & Ramsey, L. B. (2021). Planning and Conducting a Pharmacogenetics Association Study. Clinical pharmacology and therapeutics, 110(3), 688-701.
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  Pharmacogenetics (PGx) association studies are used to discover, replicate, and validate the association between an inherited genotype and a treatment outcome. The objective of this tutorial is to provide trainees and novice PGx researchers with an overview of the major decisions that need to be made when designing and conducting a PGx association study. The first critical decision is to determine whether the objective of the study is discovery, replication, or validation. Next, the researcher must identify a patient cohort that has all of the data necessary to conduct the intended analysis. Then, the investigator must select and define the treatment outcome, or phenotype, that will be analyzed. Next, the investigator must determine what genotyping approach and genetic data will be included in the analysis. Finally, the association between the genotype and phenotype is tested using some statistical analysis methodology. This tutorial is divided into five sections; each section describes commonly used approaches and provides suggestions and resources for designing and conducting a PGx association study. Successful PGx association studies are necessary to discover and validate associations between inherited genetic variation and treatment outcomes, which enable clinical translation to improve efficacy and reduce toxicity of treatment.
• Karnes, J. H., Arora, A., Feng, J., Steiner, H. E., Sulieman, L., Boerwinkle, E., Clark, C., Cicek, M., Cohn, E., Gebo, K., Loperena-Cortes, R., Ohno-Machado, L., Mayo, K., Mockrin, S., Ramirez, A., Schully, S., & Klimentidis, Y. C. (2021). Racial, ethnic, and gender differences in obesity and body fat distribution: An All of Us Research Program demonstration project. PloS one, 16(8), e0255583.
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  Differences in obesity and body fat distribution across gender and race/ethnicity have been extensively described. We sought to replicate these differences and evaluate newly emerging data from the All of Us Research Program (AoU). We compared body mass index (BMI), waist circumference, and waist-to-hip ratio from the baseline physical examination, and alanine aminotransferase (ALT) from the electronic health record in up to 88,195 Non-Hispanic White (NHW), 40,770 Non-Hispanic Black (NHB), 35,640 Hispanic, and 5,648 Asian participants. We compared AoU sociodemographic variable distribution to National Health and Nutrition Examination Survey (NHANES) data and applied the pseudo-weighting method for adjusting selection biases of AoU recruitment. Our findings replicate previous observations with respect to gender differences in BMI. In particular, we replicate the large gender disparity in obesity rates among NHB participants, in which obesity and mean BMI are much higher in NHB women than NHB men (33.34 kg/m2 versus 28.40 kg/m2 respectively; p
• Steiner, H. E., Giles, J. B., Patterson, H. K., Feng, J., El Rouby, N., Claudio, K., Marcatto, L. R., Tavares, L. C., Galvez, J. M., Calderon-Ospina, C. A., Sun, X., Hutz, M. H., Scott, S. A., Cavallari, L. H., Fonseca-Mendoza, D. J., Duconge, J., Botton, M. R., Santos, P. C., & Karnes, J. H. (2021). Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans. Frontiers in pharmacology, 12, 749786.
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  Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients ( = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, = 1.43 × 10). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone ( = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.
• Toshner, M., Church, C., Harbaum, L., Rhodes, C., Villar Moreschi, S. S., Liley, J., Jones, R., Arora, A., Batai, K., Desai, A. A., Coghlan, J. G., Gibbs, J. S., Gor, D., Gräf, S., Harlow, L., Hernandez-Sanchez, J., Howard, L. S., Humbert, M., Karnes, J., , Kiely, D. G., et al. (2021). Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH. The European respiratory journal.
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  Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
• Alkhatib, N., Sweitzer, N. K., Lee, C. S., Erstad, B., Slack, M., Gharaibeh, M., Karnes, J., Klimecki, W., Ramos, K., & Abraham, I. (2020). Ex Ante Economic Evaluation of Arg389 Genetically Targeted Treatment with Bucindolol versus Empirical Treatment with Carvedilol in NYHA III/IV Heart Failure. American journal of cardiovascular drugs : drugs, devices, and other interventions.
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  The Beta-Blocker Evaluation Survival Trial showed no survival benefit for bucindolol in New York Heart Association (NYHA) class III/IV heart failure (HF) with reduced ejection fraction, but subanalyses suggested survival benefits for non-Black subjects and Arg389 homozygotes. We conducted an ex ante economic evaluation of Arg389 targeted treatment with bucindolol versus carvidolol, complementing a previous ex ante economic evaluation of bucindolol preceded by genetic testing for the Arg389 polymorphism, in which genetic testing prevailed economically over no testing.
• El Rouby, N., Rodrigues Marcatto, L., Claudio, K., Camargo Tavares, L., Steiner, H., Botton, M. R., Lubitz, S. A., Fallon, E. N., Yee, K., Kaye, J., Scott, S. A., Karnes, J., Caleb Junior de Lima Santos, P., Duconge, J., & Cavallari, L. H. (2020). Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos. Clinical and translational science.
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  We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = -0.29, P 
• Giles, J. B., Greinacher, A., Gruel, Y., Heddle, N. M., Karnes, J. H., Kubo, M., Momozawa, Y., Mushiroda, T., Phillips, E. J., Pouplard, C., Roden, D. M., Rollin, J., Shaffer, C. M., Stanaway, I. B., Steiner, H. E., & Warkentin, T. E. (2020). Genome-Wide Association Study Identifies Variation in ABO As Risk Factor for Platelet Reactivity in Heparin-Induced Thrombocytopenia. Blood, 136(Supplement 1), 38-39. doi:10.1182/blood-2020-139651
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  Background: Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. Genome-wide association studies (GWAS) have the potential to identify genetic risk factors and generate insights into biological mechanisms of adverse drug reactions. However, published HIT GWAS are underpowered and do not include confirmation of HIT using functional assays. We aimed to identify genetic associations with HIT using a GWAS approach in two European ancestry populations tested for functional assay and PF4/heparin antibody levels. Methods: We performed a GWAS with positive functional assay as the outcome in a large discovery cohort of patients, including heparin-induced platelet aggregation (HIPA) positive cases (n=1243), antibody positive but functional assay negative controls (n=1091), and antibody negative controls (n=1718). Logistic regressions were adjusted for age, gender, and first two principal components. Significant associations from the discovery cohort (alpha=5.00x10-8) were then investigated in a replication cohort of serotonin-release assay (SRA)-confirmed HIT cases (n=173), antibody positive controls (n=125), and antibody negative controls (n=488). All patients were genotyped with the HumanOmniExpressExome BeadChip, including 9,065,510 variants after imputation and quality control. Genes near significantly associated loci were resequenced. Results: In the discovery cohort, a genome-wide significant association was observed between common variation in the ABO gene and HIPA positive status (rs505922 odds ratio 0.738 [0.668-0.816], p=2.813x10-9). This variant was also significantly associated with SRA-confirmed HIT in the replication cohort (odds ratio 0.392 [0.172-0.891], p=0.025). Meta-analysis indicated strong association of ABO variation with positive functional assay (Figure 1). Sequencing and fine-mapping of the ABO locus indicated this effect was driven by ABO blood groups, with the O blood group being a risk factor for HIT (odds ratio 1.42 [1.25-1.61], p=6.11x10-8). Conclusions: We identify common variation in ABO as a risk factor for platelet reactivity and HIT. Strong association of ABO variation may have important implications for prediction and understanding of HIT pathogenesis. Figure 1 Disclosures No relevant conflicts of interest to declare.
• Ilori, T. O., Viera, E., Wilson, J., Moreno, F., Menon, U., Ehiri, J., Peterson, R., Vemulapalli, T., StimsonRiahi, S. C., Rosales, C., Calhoun, E., Sokan, A., Karnes, J. H., Reiman, E., Ojo, A., Theodorou, A., & Ojo, T. (2020). Approach to High Volume Enrollment in Clinical Research: Experiences from an All of Us Research Program Site. Clinical and translational science, 13(4), 685-692.
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  Clinical trials and cohort studies are required to meet target recruitment of study participants within stipulated timelines, especially when the priority is to include populations traditionally unrepresented in biomedical research. By the third quarter of 2019, the University of Arizona-Banner Health Provider Organization (UA-Banner HPO) has enrolled > 30,000 core participants into the All of Us Research Program (AoURP), the research cohort of the Precision Medicine Initiative. The majority of enrolled participants meet the criteria for individuals under-represented in biomedical research. The enrollment goals were calculated based on a target of 20,000 as set by the National Institutes of Health and our health provider organization achieved enrollment numbers between 17% and 86% above the targeted daily enrollment. We evaluated enrollment methods and challenges to enrollments encountered by the UA-Banner Health Provider Organization into the AoURP. Challenges to enrollment centered around the need for high-touch engagement methods, time investment necessary for stakeholder inclusion, and the use of purely digital enrollment methods especially in populations under-represented in biomedical research. These challenges occurred at the level of the individual, provider, institutions, and community, and cumulatively impacted participant enrollment. Successful strategies for engagement and enrollment leveraged provider partners as advocates for the program. For high-volume enrollment in clinical research, it is important to engage leaders in the healthcare setting, patient providers, and tailor engagement and enrollment to potential participant needs. We emphasize the need for precision engagement and enrollment methods tailored to individual needs.
• Karnes, J. H., Rettie, A. E., Somogyi, A. A., Huddart, R., Fohner, A. E., Formea, C. M., Ta Michael Lee, M., Llerena, A., Whirl-Carrillo, M., Klein, T. E., Phillips, E. J., Mintzer, S., Gaedigk, A., Caudle, K. E., & Callaghan, J. T. (2020). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clinical pharmacology and therapeutics.
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  Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).
• Karnes, J. H., Schwantes-An, T. H., Kittles, R., & Desai, A. A. (2020). Reply to: Challenging the Role of Genetic Ancestry in Explaining Racial/Ethnic Health Disparities. American journal of respiratory and critical care medicine.
• Karnes, J. H., Wiener, H. W., Schwantes-An, T. H., Natarajan, B., Sweatt, A. J., Chaturvedi, A., Arora, A., Batai, K., Nair, V., Steiner, H. E., Giles, J. B., Yu, J., Hosseini, M., Pauciulo, M. W., Lutz, K. A., Coleman, A. W., Feldman, J., Vanderpool, R., Tang, H., , Garcia, J. G., et al. (2020). Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine, 201(11), 1407-1415.
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  Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH). Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH. Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis. After covariate adjustment, self-reported Hispanic patients ( = 290) exhibited significantly reduced mortality versus NHW patients ( = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87];  = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01];  = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients ( = 1,524) versus NHW patients ( = 8,829; OR, 0.65 [95% CI, 0.50-0.84];  = 0.001). An inpatient mortality benefit was observed for Native American patients ( = 185; OR, 0.38 [95% CI, 0.15-0.93];  = 0.034). This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.
• Caudle, K. E., Gammal, R. S., & Karnes, J. H. (2019). PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas.. Journal of the American College of Clinical Pharmacy, 2, 288–302.
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  Caudle KE, Gammal RS, Karnes JH, Afanasjeva J, Anderson KC, Barreto EF, Beavers C, Bhat S, Birrer KL, Chahine EB, Ensor CR, Flowers SA, Formea CM, George JM, Gosser RA, Hebert MF, Karaoui LR, Kolpek JH, Lee JC, Leung JG, Maldonado AQ, Minze MG, Pulk RA, Shelton CM, Sheridan M, Smith MA, Soefje S, Tellez-Corrales E, Walko CM, Cavallari LH. PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas. JACCP. 2019;2:288–302.
• Denny, J. C., Rutter, J. L., Goldstein, D. B., Philippakis, A., Smoller, J. W., Jenkins, G., & Dishman, E. (2019). The "All of Us" Research Program. The New England journal of medicine, 381(7), 668-676.
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  Knowledge gained from observational cohort studies has dramatically advanced the prevention and treatment of diseases. Many of these cohorts, however, are small, lack diversity, or do not provide comprehensive phenotype data. The All of Us Research Program plans to enroll a diverse group of at least 1 million persons in the United States in order to accelerate biomedical research and improve health. The program aims to make the research results accessible to participants, and it is developing new approaches to generate, access, and make data broadly available to approved researchers. All of Us opened for enrollment in May 2018 and currently enrolls participants 18 years of age or older from a network of more than 340 recruitment sites. Elements of the program protocol include health questionnaires, electronic health records (EHRs), physical measurements, the use of digital health technology, and the collection and analysis of biospecimens. As of July 2019, more than 175,000 participants had contributed biospecimens. More than 80% of these participants are from groups that have been historically underrepresented in biomedical research. EHR data on more than 112,000 participants from 34 sites have been collected. The All of Us data repository should permit researchers to take into account individual differences in lifestyle, socioeconomic factors, environment, and biologic characteristics in order to advance precision diagnosis, prevention, and treatment.
• Hulsen, T., Jamuar, S. S., Moody, A. R., Karnes, J. H., Varga, O., Hedensted, S., Spreafico, R., Hafler, D. A., & McKinney, E. F. (2019). From Big Data to Precision Medicine. Frontiers in medicine, 6, 34.
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  For over a decade the term "Big data" has been used to describe the rapid increase in volume, variety and velocity of information available, not just in medical research but in almost every aspect of our lives. As scientists, we now have the capacity to rapidly generate, store and analyse data that, only a few years ago, would have taken many years to compile. However, "Big data" no longer means what it once did. The term has expanded and now refers not to just large data volume, but to our increasing ability to analyse and interpret those data. Tautologies such as "data analytics" and "data science" have emerged to describe approaches to the volume of available information as it grows ever larger. New methods dedicated to improving data collection, storage, cleaning, processing and interpretation continue to be developed, although not always by, or for, medical researchers. Exploiting new tools to extract meaning from large volume information has the potential to drive real change in clinical practice, from personalized therapy and intelligent drug design to population screening and electronic health record mining. As ever, where new technology promises "Big Advances," significant challenges remain. Here we discuss both the opportunities and challenges posed to biomedical research by our increasing ability to tackle large datasets. Important challenges include the need for standardization of data content, format, and clinical definitions, a heightened need for collaborative networks with sharing of both data and expertise and, perhaps most importantly, a need to reconsider how and when analytic methodology is taught to medical researchers. We also set "Big data" analytics in context: recent advances may appear to promise a revolution, sweeping away conventional approaches to medical science. However, their real promise lies in their synergy with, not replacement of, classical hypothesis-driven methods. The generation of novel, data-driven hypotheses based on interpretable models will always require stringent validation and experimental testing. Thus, hypothesis-generating research founded on large datasets adds to, rather than replaces, traditional hypothesis driven science. Each can benefit from the other and it is through using both that we can improve clinical practice.
• Karnes, J. H., Miller, M. A., White, K. D., Konvinse, K. C., Pavlos, R. K., Redwood, A. J., Peter, J. G., Lehloenya, R., Mallal, S. A., & Phillips, E. J. (2019). Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions. Annual review of pharmacology and toxicology, 59, 463-486.
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  Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.
• Patanwala, A. E., Norwood, C., Steiner, H., Morrison, D., Li, M., Walsh, K., Martinez, M., Baker, S. E., Snyder, E. M., & Karnes, J. H. (2019). Psychological and Genetic Predictors of Pain Tolerance. Clinical and translational science, 12(2), 189-195.
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  Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological, and genetic predictors of cold noxious pain tolerance. Healthy subjects (n = 89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ-III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold-pressor test in a 1-2°C water bath for a maximum of 3 minutes. The primary outcome measure was pain tolerance, defined as the maximum duration of time subjects left their nondominant hand in the cold-water bath. Cox proportional hazards regression indicated that female sex, Asian race, and increasing PCS and FPQ-III scores were associated with lower pain tolerance. No candidate SNP was significantly associated with pain tolerance. Future genetic studies should include demographic and psychological variables as confounders in experimental pain models.
• Ramamoorthy, A., Karnes, J. H., Finkel, R., Blanchard, R., & Pacanowski, M. (2019). Evolution of Next Generation Therapeutics: Past, Present, and Future of Precision Medicines. Clinical and translational science, 12(6), 560-563.
• Ramamoorthy, A., Yee, S. W., & Karnes, J. (2019). Unveiling the Genetic Architecture of Human Disease for Precision Medicine. Clinical and translational science, 12(1), 3-5.
• Rhodes, C. J., Batai, K., Bleda, M., Haimel, M., Southgate, L., Germain, M., Pauciulo, M. W., Hadinnapola, C., Aman, J., Girerd, B., Arora, A., Knight, J., Hanscombe, K. B., Karnes, J. H., Kaakinen, M., Gall, H., Ulrich, A., Harbaum, L., Cebola, I., , Ferrer, J., et al. (2019). Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. The Lancet. Respiratory medicine, 7(3), 227-238.
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  Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
• Vanderpool, R. R., Arora, A., Batai, K., Benza, R. L., Chaturvedi, A., Coleman, A. W., Desai, A. A., Feldman, J., Garcia, J. G., Giles, J. B., Hosseini, M., Karnes, J. H., Kittles, R. A., Lutz, K. A., Nair, V., Natarajan, B., Nichols, B., Pauciulo, M. W., Rischard, F., , Schwantes-an, T., et al. (2019). Abstract 10124: Genetic Admixture and Survival in Diverse Populations With Pulmonary Arterial Hypertension (PAH). Circulation.
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  Introduction: Limited information is available on racial/ethnic differences in PAH. We report effects of race/ethnicity on mortality and disease outcomes with PAH. Methods: Group 1 PAH patients wer...
• Abraham, I. L., Sweitzer, N. K., Klimecki, W., Karnes, J. H., Erstad, B. L., Slack, M. K., Gharaibeh, M., Ramos, K., Alkhatib, N., Abraham, I. L., Sweitzer, N. K., Klimecki, W., Karnes, J. H., Erstad, B. L., Slack, M. K., Gharaibeh, M., Ramos, K., & Alkhatib, N. (2018). Economic evaluation of genetic testing for Arg389 in the management of stage III/IV heart failure.. Expert Review of Precision Medicine and Drug Development, 3, 319-329.
• Bime, C., Pouladi, N., Sammani, S., Batai, K., Casanova, N., Zhou, T., Kempf, C. L., Sun, X., Camp, S. M., Wang, T., Kittles, R. A., Lussier, Y. A., Jones, T. K., Reilly, J. P., Meyer, N. J., Christie, J. D., Karnes, J. H., Gonzalez-Garay, M., Christiani, D. C., , Yates, C. R., et al. (2018). Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor. American journal of respiratory and critical care medicine, 197(11), 1421-1432.
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  Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.
• Karnes, J. H. (2018). Pharmacogenetics to prevent heparin-induced thrombocytopenia: what do we know?. Pharmacogenomics, 19(18), 1413-1422.
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  Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated adverse reaction to heparin anticoagulants. The inability to predict HIT represents a considerable liability associated with heparin administration. Genetic studies of HIT are challenging due to the scarcity of true HIT cases, potential for misclassification, and many environmental risk factors. Genetic studies have not consistently identified risk alleles for HIT, the production of platelet factor 4/heparin antibodies or the thromboembolic complications of HIT. Genes implicated in HIT and platelet factor 4/heparin antibody levels include FCGR2A, TDAG8, HLA-DR and others. Compelling evidence also suggests that the FCGR2A H131R polymorphism is associated with HIT-related thrombosis. There is a need for well-powered, multiethnic studies with laboratory confirmation of HIT, detailed patient- and drug-specific data, and inclusion of both serologic and thromboembolic outcomes. Genomic biomarkers identified from such studies offer the possibility of shifting current clinical practice paradigms from early detection and treatment to prevention.
• Karnes, J., Ramamoorthy, A., & Yee, S. W. (2018). Unveiling the Genetic Architecture of Human Disease for Precision Medicine. Clinical and Translational Science, 12(1), 3-5. doi:10.1111/cts.12593
• Lynn, H., Sun, X., Ayshiev, D., Siegler, J. H., Rizzo, A. N., Karnes, J. H., Gonzales Garay, M., Wang, T., Casanova, N., Camp, S. M., Ellis, N. A., & Garcia, J. G. (2018). Single nucleotide polymorphisms in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PloS one, 13(8), e0200916.
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  Pseudogenes are paralogues of functional genes historically viewed as defunct due to either the lack of regulatory elements or the presence of frameshift mutations. Recent evidence, however, suggests that pseudogenes may regulate gene expression, although the functional role of pseudogenes remains largely unknown. We previously reported that MYLKP1, the pseudogene of MYLK that encodes myosin light chain kinase (MLCK), is highly expressed in lung and colon cancer cell lines and tissues but not in normal lung or colon. The MYLKP1 promoter is minimally active in normal bronchial epithelial cells but highly active in lung adenocarcinoma cells. In this study, we further validate MYLKP1 as an oncogene via elucidation of the functional role of MYLKP1 genetic variants in colon cancer risk.
• Mosley, J. D., Feng, Q., Wells, Q. S., Van Driest, S. L., Shaffer, C. M., Edwards, T. L., Bastarache, L., Wei, W. Q., Davis, L. K., McCarty, C. A., Thompson, W., Chute, C. G., Jarvik, G. P., Gordon, A. S., Palmer, M. R., Crosslin, D. R., Larson, E. B., Carrell, D. S., Kullo, I. J., , Pacheco, J. A., et al. (2018). A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers. Nature communications, 9(1), 3522.
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  Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.
• Arora, A., Batai, K., Desai, A. A., Garcia, J. G., Karnes, J. H., Kaye, J., Nair, V., Nichols, W. C., Pauciulo, M., Steiner, H. E., & Yuan, J. X. (2017). Abstract 24015: Genome-Wide Association Study of Vasodilator Response in Pulmonary Arterial Hypertension. Circulation, 136(suppl_1). doi:10.1161/circ.136.suppl_1.24015
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  Introduction: Pulmonary arterial hypertension (PAH) is a rare and fatal disease associated with variable therapeutic response, suggesting a genetic contribution. Vasodilator-responsive PAH accounts...
• Karnes, J. H., Bastarache, L., Shaffer, C. M., Gaudieri, S., Xu, Y., Glazer, A. M., Mosley, J. D., Zhao, S., Raychaudhuri, S., Mallal, S., Ye, Z., Mayer, J. G., Brilliant, M. H., Hebbring, S. J., Roden, D. M., Phillips, E. J., & Denny, J. C. (2017). Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. SCIENCE TRANSLATIONAL MEDICINE, 9(389).
• Karnes, J. H., Bastarache, L., Shaffer, C. M., Gaudieri, S., Xu, Y., Glazer, A. M., Mosley, J. D., Zhao, S., Raychaudhuri, S., Mallal, S., Ye, Z., Mayer, J. G., Brilliant, M. H., Hebbring, S. J., Roden, D. M., Phillips, E. J., & Denny, J. C. (2017). Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Science translational medicine, 9(389).
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  Although many phenotypes have been associated with variants in human leukocyte antigen (HLA) genes, the full phenotypic impact of HLA variants across all diseases is unknown. We imputed HLA genomic variation from two populations of 28,839 and 8431 European ancestry individuals and tested association of HLA variation with 1368 phenotypes. A total of 104 four-digit and 92 two-digit HLA allele phenotype associations were significant in both discovery and replication cohorts, the strongest being HLA-DQB1*03:02 and type 1 diabetes. Four previously unidentified associations were identified across the spectrum of disease with two- and four-digit HLA alleles and 10 with nonsynonymous variants. Some conditions associated with multiple HLA variants and stronger associations with more severe disease manifestations were identified. A comprehensive, publicly available catalog of clinical phenotypes associated with HLA variation is provided. Examining HLA variant disease associations in this large data set allows comprehensive definition of disease associations to drive further mechanistic insights.
• Karnes, J. H., Erstad, B. L., Aljabri, A., Huckleberry, Y., Gharaibeh, M., Kutbi, H. I., Raz, Y., Yun, S., & Abraham, I. L. (2017). Medical Management of Heparin-Induced Thrombocytopenia: Pharmacoeconomic Considerations. Blood e-letter (19 June, 2017). Blood.
• Karnes, J. H., Shaffer, C. M., Bastarache, L., Gaudieri, S., Glazer, A. M., Steiner, H. E., Mosley, J. D., Mallal, S., Denny, J. C., Phillips, E. J., & Roden, D. M. (2017). Comparison of HLA allelic imputation programs. PloS one, 12(2), e0172444.
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  Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.
• Karnes, J. H., Shaffer, C. M., Cronin, R., Bastarache, L., Gaudieri, S., James, I., Pavlos, R., Steiner, H. E., Mosley, J. D., Mallal, S., Denny, J. C., Phillips, E. J., & Roden, D. M. (2017). Influence of Human Leukocyte Antigen (HLA) Alleles and Killer Cell Immunoglobulin-Like Receptors (KIR) Types on Heparin-Induced Thrombocytopenia (HIT). Pharmacotherapy, 37(9), 1164-1171.
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  Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin. Variation in human leukocyte antigen (HLA) genes is now used to prevent immune-mediated adverse drug reactions. Combinations of HLA alleles and killer cell immunoglobulin-like receptors (KIR) are associated with multiple autoimmune diseases and infections. The objective of this study is to evaluate the association of HLA alleles and KIR types, alone or in the presence of different HLA ligands, with HIT. HIT cases and heparin-exposed controls were identified in BioVU, an electronic health record coupled to a DNA biobank. HLA sequencing and KIR type imputation using Illumina OMNI-Quad data were performed. Odds ratios for HLA alleles and KIR types and HLA*KIR interactions using conditional logistic regressions were determined in the overall population and by race/ethnicity. Analysis was restricted to KIR types and HLA alleles with a frequency greater than 0.01. The p values for HLA and KIR association were corrected by using a false discovery rate q
• Kaye, J. B., Schultz, L. E., Steiner, H. E., Kittles, R. A., Cavallari, L. H., & Karnes, J. H. (2017). Warfarin Pharmacogenomics in Diverse Populations. Pharmacotherapy.
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  Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African-Americans (AAs) and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies and effects of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence with warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. This article is protected by copyright. All rights reserved.
• Wells, Q. S., Veatch, O. J., Fessel, J. P., Joon, A. Y., Levinson, R. T., Mosley, J. D., Held, E. P., Lindsay, C. S., Shaffer, C. M., Weeke, P. E., Glazer, A. M., Bersell, K. R., Van Driest, S. L., Karnes, J. H., Blair, M. A., Lagrone, L. W., Su, Y. R., Bowton, E. A., Feng, Z., , Ky, B., et al. (2017). Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults. Pharmacogenetics and genomics, 27(7), 247-254.
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  Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy.
• Abraham, I., Aljabri, A., Erstad, B. L., Gharaibeh, M., Huckleberry, Y., Karnes, J. H., Kutbi, H. I., Raz, Y., & Yun, S. (2016). Abstract 15582: Cost-effectiveness of Anticoagulants for the Management of Suspected Heparin-induced Thrombocytopenia in the US. Circulation, 134.
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  Introduction: Despite the availability of multiple non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT), little data are available comparing the cost effectiveness of these agents. This analysis is particularly important considering differences in risks of adverse effects, routes of administration, requirements for phlebotomy and laboratory monitoring, and overall drug costs. We conducted a cost-effectiveness analysis of argatroban, bivalirudin, and fondaparinux for the treatment of suspected HIT. Methods: A three-arm decision-tree model was developed that employs standard practices for anticoagulation monitoring. We incorporated published data on drug efficacy and probability of HIT-related thromboembolism and major bleeding. We considered both institutional costs and Average Wholesale Price (AWP) and performed probabilistic sensitivity analysis (PSA) to address any uncertainty in model parameters. Results: Using institutional costs, fondaparinux outperformed both argatroban and bivalirudin in terms of cost ($151 vs. $1,250 and $1,466, respectively) and adverse events averted (0.9989 vs. 0.9957 and 0.9947, respectively). Results were consistent when AWP was used, with fondaparinux being less expensive ($555 vs. $3,081 and $2,187, respectively) and more effective in terms of adverse events averted (0.9989 vs. 0.9957 and 0.9947, respectively). The PSA confirmed our findings using both institutional costs and AWP. Conclusions: Fondaparinux subcutaneous injection afforded significant advantages in terms of cost savings and adverse events averted compared to intravenous argatroban or bivalirudin infusions. Our data strongly suggest potential cost savings with fondaparinux and underscore the critical need for larger clinical studies of fondaparinux in the treatment of suspected HIT.
• Aljabri, A., Huckleberry, Y., Karnes, J. H., Gharaibeh, M., Kutbi, H. I., Raz, Y., Yun, S., Abraham, I., & Erstad, B. (2016). Cost-effectiveness of anticoagulants for suspected heparin-induced thrombocytopenia in the United States. Blood, 128(26), 3043-3051.
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  Despite the availability of multiple nonheparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT), few data are available comparing the cost-effectiveness of these agents. This analysis is particularly important when considering differences in the risk of adverse effects, routes of administration, requirements for phlebotomy and laboratory monitoring, and overall drug costs. We conducted a cost-effectiveness analysis of argatroban, bivalirudin, and fondaparinux for the treatment of suspected HIT from the institutional perspective. A 3-arm decision-tree model was developed that employs standard practices for anticoagulation monitoring. We incorporated published data on drug efficacy and probability of HIT-related thromboembolism and major bleeding. We considered both institutional costs and average wholesale price (AWP) and performed probabilistic sensitivity analyses (PSA) to address any uncertainty in model parameters. Using institutional costs, fondaparinux prevailed over both argatroban and bivalirudin in terms of cost ($151 vs $1250 and $1466, respectively) and adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). Results were consistent when AWP was used, with fondaparinux being less expensive ($555 vs $3081 and $2187, respectively) and more effective in terms of adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). The PSA confirmed our findings using both institutional costs and AWP. In conclusion, fondaparinux subcutaneous injection afforded significant advantages in terms of cost savings and adverse events averted compared with IV argatroban or bivalirudin infusions. Our data strongly suggest potential cost savings with fondaparinux and underscore the critical need for larger clinical studies of fondaparinux in the treatment of suspected HIT.
• Glazer, A. M., Hemler, J. A., Karnes, J. H., Kendall, P. L., Mallal, S. A., Marston, E. S., & Phillips, E. J. (2016). A Study of Immunogenetic Associations with Peanut Allergy Utilizing a Novel DNA Repository. The Journal of Allergy and Clinical Immunology, 137(2), AB25. doi:10.1016/j.jaci.2015.12.080
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  S A T U R D A Y Jonathan A. Hemler, MD, Elizabeth S. Marston, MD, Jason H. Karnes, PhD, Andrew M. Glazer, PhD, Elizabeth J. Phillips, MD, Simon A. Mallal, MBBS, Peggy L. Kendall, MD; Vanderbilt University School of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Nashville, TN, Vanderbilt University School of Medicine, Monroe Carrell, Jr. Children’s Hospital Pediatric Residency Program, Nashville, TN, Vanderbilt University School of Medicine, Division of Clinical Pharmacology, Department of Medicine, Nashville, TN, Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Australia, Vanderbilt University School of Medicine, Division of Infectious Diseases, Department of Medicine, Nashville, TN, Vanderbilt University School of Medicine, Center for Translational Immunology and Infectious Diseases, Nashville, TN, Vanderbilt University School of Medicine, Department of Pathology, Microbiology and Immunology, Nashville, TN. RATIONALE: A fundamental knowledge gap exists regarding genetic causes of peanut allergy (PA). Large genetic databases now make it possible to conduct detailed human genome studies to identify contributors to disease. METHODS: BioVU, a unique biorepository of >200,000 DNA samples matched to de-identified electronic medical records (EMR), was used to identify subjects for study of HLA alleles associated with peanut allergy (PA). 65 PA patients and 170 peanut tolerant controls (PC) were identified in BioVU using an algorithm ratified by expert review. Of these, 16 PA and 43 PC self-identified White patients had genotypic data available for analysis. HLA alleles were imputed from Illumina HumanExome BeadChip data using SNP2HLA. HLA allele associations were tested in a dominant model with PLINK with significance considered at alpha50.05. RESULTS: No significant associations (p
• Mosley, J. D., Shaffer, C. M., Van Driest, S. L., Weeke, P. E., Wells, Q. S., Karnes, J. H., Velez Edwards, D. R., Wei, W., Teixeira, P. L., Bastarache, L., Crawford, D. C., Li, R., Manolio, T. A., Bottinger, E. P., McCarty, C. A., Linneman, J. G., Brilliant, M. H., Pacheco, J. A., Thompson, W., , Chisholm, R. L., et al. (2016). A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough. The pharmacogenomics journal.
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  The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.The Pharmacogenomics Journal advance online publication, 14 July 2015; doi:10.1038/tpj.2015.51.
• Mosley, J. D., Shaffer, C. M., Van, D., Weeke, P. E., Wells, Q. S., Karnes, J. H., Edwards, D., Wei, W., Teixeira, P. L., Bastarache, L., Crawford, D. C., Li, R., Manolio, T. A., Bottinger, E. P., McCarty, C. A., Linneman, J. G., Brilliant, M. H., Pacheco, J. A., Thompson, W., , Chisholm, R. L., et al. (2016). A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough. PHARMACOGENOMICS JOURNAL, 16(3), 231-237.
• Mosley, J. D., Witte, J. S., Larkin, E. K., Bastarache, L., Shaffer, C. M., Karnes, J. H., Stein, C. M., Phillips, E., Hebbring, S. J., Brilliant, M. H., Mayer, J., Ye, Z., Roden, D. M., & Denny, J. C. (2016). Identifying genetically driven clinical phenotypes using linear mixed models. Nature communications, 7, 11433.
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  We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q
• Bowton, E. A., Denny, J. C., Driest, S. L., Karnes, J. H., Mosley, J. D., Peterson, J. F., Roden, D. M., & Weeke, P. E. (2015). Erratum to Using systems approaches to address challenges for clinical implementation of pharmacogenomics[WIREs Syst Biol Med (2014), 6:125-135. doi: 10.1002/wsbm.1255]. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 7(3), 139-139. doi:10.1002/wsbm.1298
• Cronin, R. M., Denny, J. C., Karnes, J. H., Mallal, S., Mosley, J. D., Phillips, E. J., Roden, D. M., & Shaffer, C. M. (2015). Abstract 13476: Association of HLA-DRB3*01:01 With Heparin-Induced Thrombocytopenia. Circulation.
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  Introduction: Variation in the human leukocyte antigen (HLA) region is now used clinically to prevent immune-mediated adverse drug reactions. Heparin-induced thrombocytopenia (HIT) is an unpredicta...
• Karnes, J. H., Cronin, R. M., Rollin, J., Teumer, A., Pouplard, C., Shaffer, C. M., Blanquicett, C., Bowton, E. A., Cowan, J. D., Mosley, J. D., Van Driest, S. L., Weeke, P. E., Wells, Q. S., Bakchoul, T., Denny, J. C., Greinacher, A., Gruel, Y., & Roden, D. M. (2015). A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record. Thrombosis and haemostasis, 113(4), 772-81.
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  Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. No genome-wide evaluations have been performed to identify potential genetic influences on HIT. Here, we performed a genome-wide association study (GWAS) and candidate gene study using HIT cases and controls identified using electronic medical records (EMRs) coupled to a DNA biobank and attempted to replicate GWAS associations in an independent cohort. We subsequently investigated influences of GWAS-associated single nucleotide polymorphisms (SNPs) on PF4/heparin antibodies in non-heparin treated individuals. In a recessive model, we observed significant SNP associations (odds ratio [OR] 18.52; 95% confidence interval [CI] 6.33-54.23; p=3.18×10(-9)) with HIT near the T-Cell Death-Associated Gene 8 (TDAG8). These SNPs are in linkage disequilibrium with a missense TDAG8 SNP. TDAG8 SNPs trended toward an association with HIT in replication analysis (OR 5.71; 0.47-69.22; p=0.17), and the missense SNP was associated with PF4/heparin antibody levels and positive PF4/heparin antibodies in non-heparin treated patients (OR 3.09; 1.14-8.13; p=0.02). In the candidate gene study, SNPs at HLA-DRA were nominally associated with HIT (OR 0.25; 0.15-0.44; p=2.06×10(-6)). Further study of TDAG8 and HLA-DRA SNPs is warranted to assess their influence on the risk of developing HIT.
• Karnes, J. H., Cronin, R. M., Rollin, J., Teumer, A., Pouplard, C., Shaffer, C. M., Blanquicett, C., Bowton, E. A., Cowan, J. D., Mosley, J. D., Van, D., Weeke, P. E., Wells, Q. S., Bakchou, T., Denny, J. C., Greinacher, A., Gruel, Y., & Roden, D. M. (2015). A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record. THROMBOSIS AND HAEMOSTASIS, 113(4), 772-781.
• Sanders, M. L., Karnes, J. H., Denny, J. C., Roden, D. M., Ikizler, T. A., & Birdwell, K. A. (2015). Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients. Transplantation direct, 1(4).
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  Cutaneous squamous cell carcinoma (cSCC) occurs with higher frequency and recurrence rates, increased morbidity and mortality, and more aggressive metastasis in kidney and heart transplant recipients compared to the general population but all transplant recipients do not develop cSCC. In addition, the phenotypic expression of cSCC among transplant recipients can vary between mild disease to extensive recurrent metastatic disease. These clinically observed differences in occurrence and severity of cSCC among transplant recipients suggest the possibility that an underlying genetic component might modify risk.
• Bowton, E., Cowan, J. D., Cronin, R. M., Denny, J. C., Driest, S. L., Karnes, J. H., Mosley, J. D., Roden, D. M., Shaffer, C. M., Weeke, P., & Wells, Q. S. (2014). Abstract 11449: Influence of Exonic Variation on Heparin-Induced Thrombocytopenia. Circulation.
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  Introduction: Heparin-induced thrombocytopenia (HIT) is an immune-mediated, potentially fatal adverse effect of heparin treatment. Here we test the hypotheses that exonic variants are associated wi...
• Bowton, E., Field, J. R., Wang, S., Schildcrout, J. S., Van Driest, S. L., Delaney, J. T., Cowan, J., Weeke, P., Mosley, J. D., Wells, Q. S., Karnes, J. H., Shaffer, C., Peterson, J. F., Denny, J. C., Roden, D. M., & Pulley, J. M. (2014). Biobanks and electronic medical records: enabling cost-effective research. Science translational medicine, 6(234), 234cm3.
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  The use of electronic medical record data linked to biological specimens in health care settings is expected to enable cost-effective and rapid genomic analyses. Here, we present a model that highlights potential advantages for genomic discovery and describe the operational infrastructure that facilitated multiple simultaneous discovery efforts.
• Bowton, E., Field, J. R., Wang, S., Schildcrout, J. S., Van, D., Delaney, J. T., Cowan, J., Weeke, P., Mosley, J. D., Wells, Q. S., Karnes, J. H., Shaffer, C., Peterson, J. F., Denny, J. C., Roden, D. M., & Pulley, J. M. (2014). Biobanks and Electronic Medical Records: Enabling Cost-Effective Research. SCIENCE TRANSLATIONAL MEDICINE, 6(234).
• Gong, Y., McDonough, C. W., Beitelshees, A. L., Karnes, J. H., O'Connell, J. R., Turner, S. T., Chapman, A. B., Gums, J. G., Bailey, K. R., Boerwinkle, E., Johnson, J. A., & Cooper-DeHoff, R. M. (2014). PROX1 gene variant is associated with fasting glucose change after antihypertensive treatment. Pharmacotherapy, 34(2), 123-30.
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  To assess the relationship of the 33 single nucleotide polymorphisms (SNPs) previously associated with fasting glucose in Caucasians in genome-wide association studies (GWAS) with glucose response to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes.
• Gubbins, P. O., Micek, S. T., Badowski, M., Cheng, J., Gallagher, J., Johnson, S. G., Karnes, J. H., Lyons, K., Moore, K. G., & Strnad, K. (2014). Innovation in Clinical Pharmacy Practice and Opportunities for Academic-Practice Partnership. PHARMACOTHERAPY, 34(5), E45-E54.
• Gubbins, P. O., Micek, S. T., Badowski, M., Cheng, J., Gallagher, J., Johnson, S. G., Karnes, J. H., Lyons, K., Moore, K. G., & Strnad, K. (2014). Innovation in clinical pharmacy practice and opportunities for academic--practice partnership. Pharmacotherapy, 34(5), e45-54.
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  Clinical pharmacy has a rich history of advancing practice through innovation. These innovations helped to mold clinical pharmacy into a patient-centered discipline recognized for its contributions to improving medication therapy outcomes. However, innovations in clinical pharmacy practice have now waned. In our view, the growth of academic–practice partnerships could reverse this trend and stimulate innovation among the next generation of pioneering clinical pharmacists. Although collaboration facilitates innovation,academic institutions and health care systems/organizations are not taking full advantage of this opportunity. The academic–practice partnership can be optimized by making both partners accountable for the desired outcomes of their collaboration, fostering symbiotic relationships that promote value-added clinical pharmacy services and emphasizing continuous quality improvement in the delivery of these services. Optimizing academic–practice collaboration on a broader scale requires both partners to adopt a culture that provides for dedicated time to pursue innovation, establishes mechanisms to incubate ideas, recognizes where motivation and vision align, and supports the purpose of the partnership. With appropriate leadership and support, a shift in current professional education and training practices, and a commitment to cultivate future innovators, the academic–practice partnership can develop new and innovative practice advancements that will improve patient outcomes.
• Karnes, J. H., Gong, Y., Arwood, M. J., Gums, J. G., Hall, K. L., Limacher, M. C., Johnson, J. A., & Cooper-DeHoff, R. M. (2014). Alteration in fasting glucose after prolonged treatment with a thiazide diuretic. DIABETES RESEARCH AND CLINICAL PRACTICE, 104(3), 363-369.
• Karnes, J. H., Gong, Y., Arwood, M. J., Gums, J. G., Hall, K. L., Limacher, M. C., Johnson, J. A., & Cooper-DeHoff, R. M. (2014). Alteration in fasting glucose after prolonged treatment with a thiazide diuretic. Diabetes research and clinical practice, 104(3), 363-9.
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  Thiazide diuretics are recommended as first line antihypertensive treatment, but may contribute to new onset diabetes. We aimed to describe change in fasting glucose (FG) during prolonged thiazide treatment in an observational setting.
• Karnes, J. H., Van Driest, S., Bowton, E. A., Weeke, P. E., Mosley, J. D., Peterson, J. F., Denny, J. C., & Roden, D. M. (2014). Using systems approaches to address challenges for clinical implementation of pharmacogenomics. Wiley interdisciplinary reviews. Systems biology and medicine, 6(2), 125-35.
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  Many genetic variants have been shown to affect drug response through changes in drug efficacy and likelihood of adverse effects. Much of pharmacogenomic science has focused on discovering and clinically implementing single gene variants with large effect sizes. Given the increasing complexities of drug responses and their variability, a systems approach may be enabling for discovery of new biology in this area. Further, systems approaches may be useful in addressing challenges in moving these data to clinical implementation, including creation of predictive models of drug response phenotypes, improved clinical decision-making through complex biological models, improving strategies for integrating genomics into clinical practice, and evaluating the impact of implementation programs on public health.
• Karnes, J. H., Van, D. S., Bowton, E. A., Weeke, P. E., Mosley, J. D., Peterson, J. F., Denny, J. C., & Roden, D. M. (2014). Using systems approaches to address challenges for clinical implementation of pharmacogenomics. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE, 6(2), 125-135.
• Weeke, P., Mosley, J. D., Hanna, D., Delaney, J. T., Shaffer, C., Wells, Q. S., Van Driest, S., Karnes, J. H., Ingram, C., Guo, Y., Shyr, Y., Norris, K., Kannankeril, P. J., Ramirez, A. H., Smith, J. D., Mardis, E. R., Nickerson, D., George, A. L., & Roden, D. M. (2014). Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome. Journal of the American College of Cardiology, 63(14), 1430-7.
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  The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes.
• Weeke, P., Mosley, J. D., Hanna, D., Delaney, J. T., Shaffer, C., Wells, Q. S., Van, D. S., Karnes, J. H., Ingram, C., Guo, Y., Shyr, Y. u., Norris, K., Kannankeril, P. J., Ramirez, A. H., Smith, J. D., Mardis, E. R., Nickerson, D., George Jr., A. L., & Roden, D. M. (2014). Exome Sequencing Implicates an Increased Burden of Rare Potassium Channel Variants in the Risk of Drug-Induced Long QT Interval Syndrome. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 63(14), 1430-1437.
• Bowton, E., Denny, J. C., Driest, S. L., Karnes, J. H., Mosley, J. D., Roden, D. M., Shaffer, C. M., Weeke, P., & Wells, Q. S. (2013). Abstract 15509: Genomwide-Association Identifies a Novel Locus for Anthracycline Cardiotoxicity. Circulation, 128.
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  Anthracyclines are important chemotherapeutic agents, but use can be limited by cardiotoxicity. Prior candidate gene studies have identified loci linked to toxicity. Here we used genome-wide associ...
• Delaney, J. T., Driest, S. L., George, A. L., Guo, Y., Hanna, D. B., Ingram, C., Kannankeril, P. J., Karnes, J. H., Mardis, E. R., Mosley, J. D., Nickerson, D. A., Norris, K., Ramirez, A. H., Roden, D. M., Shaffer, C. M., Shyr, Y., Smith, J. D., Weeke, P., & Wells, Q. S. (2013). Abstract 11082: Exome Sequencing Implicates the Burden of Rare Potassium Channel Variants in the Risk of Drug Induced Long QT Syndrome. Circulation, 128.
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  Background: Drug-induced long QT syndrome (diLQTS) is associated with the potentially fatal arrhythmia torsades de pointes (TdP). The contribution of rare genetic variants to the underlying genetic...
• Gong, Y., McDonough, C. W., Beitelshees, A. L., Karnes, J. H., O'Connell, J. R., Turner, S. T., Chapman, A. B., Gums, J. G., Bailey, K. R., Boerwinkle, E., Johnson, J. A., & Cooper-DeHoff, R. M. (2013). PROX1 Gene Variant is Associated with Fasting Glucose Change After Antihypertensive Treatment. PHARMACOTHERAPY, 34(2), 123-130.
• Karnes, J. H., Gong, Y., Pacanowski, M. A., McDonough, C. W., Arwood, M. J., Langaee, T. Y., Pepine, C. J., Johnson, J. A., & Cooper-DeHoff, R. M. (2013). Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes. PHARMACOGENETICS AND GENOMICS, 23(12), 697-705.
• Karnes, J. H., Gong, Y., Pacanowski, M. A., McDonough, C. W., Arwood, M. J., Langaee, T. Y., Pepine, C. J., Johnson, J. A., & Cooper-Dehoff, R. M. (2013). Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes. Pharmacogenetics and genomics, 23(12), 697-705.
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  Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD.
• Karnes, J. H., Langaee, T. Y., McDonough, C. W., Chang, S., Ramos, M., Catlin Jr., J. R., Casanova, O. E., Gong, Y., Pepine, C. J., Johnson, J. A., & Cooper-DeHoff, R. M. (2013). Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort. JOURNAL OF TRANSLATIONAL MEDICINE, 11.
• Karnes, J. H., Langaee, T. Y., McDonough, C. W., Chang, S., Ramos, M., Catlin, J. R., Casanova, O. E., Gong, Y., Pepine, C. J., Johnson, J. A., & Cooper-Dehoff, R. M. (2013). Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort. Journal of translational medicine, 11, 12.
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  Recently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).
• Karnes, J. H., McDonough, C. W., Gong, Y., Vo, T. T., Langaee, T. Y., Chapman, A. B., Gums, J. G., Beitelshees, A. L., Bailey, K. R., Del-Aguila, J. L., Boerwinkle, E. A., Pepine, C. J., Turner, S. T., Johnson, J. A., & Cooper-DeHoff, R. M. (2013). Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment. PHARMACOGENOMICS JOURNAL, 13(5), 430-436.
• Karnes, J. H., McDonough, C. W., Gong, Y., Vo, T. T., Langaee, T. Y., Chapman, A. B., Gums, J. G., Beitelshees, A. L., Bailey, K. R., Del-Aguila, J. L., Boerwinkle, E. A., Pepine, C. J., Turner, S. T., Johnson, J. A., & Cooper-DeHoff, R. M. (2013). Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment. The pharmacogenomics journal, 13(5), 430-6.
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  Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.
• Mosley, J. D., Van Driest, S. L., Larkin, E. K., Weeke, P. E., Witte, J. S., Wells, Q. S., Karnes, J. H., Guo, Y., Bastarache, L., Olson, L. M., McCarty, C. A., Pacheco, J. A., Jarvik, G. P., Carrell, D. S., Larson, E. B., Crosslin, D. R., Kullo, I. J., Tromp, G., Kuivaniemi, H., , Carey, D. J., et al. (2013). Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data. PloS one, 8(12), e81503.
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  A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF
• Mosley, J. D., Van, D., Larkin, E. K., Weeke, P. E., Witte, J. S., Wells, Q. S., Karnes, J. H., Guo, Y., Bastarache, L., Olson, L. M., McCarty, C. A., Pacheco, J. A., Jarvik, G. P., Carrell, D. S., Larson, E. B., Crosslin, D. R., Kullo, I. J., Tromp, G., Kuivaniemi, H., , Carey, D. J., et al. (2013). Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data. PLOS ONE, 8(12).
• Karnes, J. H., & Cooper-DeHoff, R. M. (2009). Antihypertensive medications: benefits of blood pressure lowering and hazards of metabolic effects. Expert review of cardiovascular therapy, 7(6), 689-702.
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  Blood pressure reduction is associated with significant reduction in adverse cardiovascular outcomes. Certain blood pressure-lowering drugs have adverse effects on glucose homeostasis, and have been associated with the development of both prediabetes and diabetes during use. There is controversy over the significance of diabetes that develops during treatment with antihypertensives and whether the benefits of blood pressure reduction offset the hazards of dysglycemia that can lead to diabetes. Many treatment guidelines have recently undergone revisions to include consideration for the metabolic effects of antihypertensive drugs, particularly in high-risk populations. This review summarizes the data related to the benefits of blood pressure reduction as well as the adverse metabolic effects and new-onset diabetes associated with some medications.
• Brunner, M., Cooper-DeHoff, R. M., Gong, Y., Karnes, J. H., Langaee, T. Y., Pepine, C. J., & Johnson, J. A. (2007). Factors influencing blood pressure response to trandolapril add-on therapy in patients taking verapamil SR (from the International Verapamil SR/Trandolapril [INVEST] study). AMERICAN JOURNAL OF CARDIOLOGY, 99(11), 1549-1554.
• Brunner, M., Cooper-DeHoff, R. M., Gong, Y., Karnes, J. H., Langaee, T. Y., Pepine, C. J., Johnson, J. A., & , I. I. (2007). Factors influencing blood pressure response to trandolapril add-on therapy in patients taking verapamil SR (from the International Verapamil SR/Trandolapril [INVEST] Study). The American journal of cardiology, 99(11), 1549-54.
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  Factors such as age and race/ethnicity might influence blood pressure (BP) response to drugs. Therapeutic response to the angiotensin-converting enzyme inhibitor trandolapril used as add-on therapy to stable calcium channel blocker therapy with verapamil sustained release 240 mg was addressed in a racially/ethnically diverse group of 1,832 hypertensive patients with coronary artery disease. Furthermore, the association with a polymorphism (1166A-->C) in the angiotensin II type 1 receptor gene (AGTR1) was tested. BP response was compared between groups using analysis of covariance after adjustment for covariates associated with BP response. Genotyping was performed using polymerase chain reaction and pyrosequencing. Trandolapril decreased mean unadjusted systolic and diastolic BPs by -9.1 +/- 17.3 (SD) and -4.1 +/- 10.1 mm Hg, respectively. The percentage of patients with BP under control (
• Brunner, M., Cooper-dehoff, R. M., Cooperdehoff, R., Gong, Y., Johnson, J. A., Karnes, J. H., Langaee, T. Y., & Pepine, C. J. (2006). PI-26Association of angiotensin II type I receptor (AGTR1) 1166A>C polymorphism with blood pressure response to ACE inhibitor in a subgroup of patients of the international verapamil SR/trandolapril study (INVEST). Clinical Pharmacology & Therapeutics, 79(2), P14-P14. doi:10.1016/j.clpt.2005.12.047

Proceedings Publications

• Camp, S. M., Casanova, N. G., Coletta, D., Ellid, N., Garcia, J. G., Karnes, J. H., Lynn, H., & Sun, X. (2020). Nicotinamide Phosphoribosyl Transferase (NAMPT) Genotype-Phenotype Haplotype and Elevated Extracellular NAMPT Levels Predict Mortality Outcomes in Acute Respiratory Distress Syndrome (ARDS). In C17. NOVEL APPROACHES TO ACUTE LUNG INJURY.
• Arora, A., Batai, K., Brittain, E. L., Coleman, A. W., Desai, A. A., Garcia, J. G., Geraci, M. W., Halladay, S., Hemnes, A. R., Karnes, J. H., Kittles, R., Lutz, K. A., Nichols, W. C., Pauciulo, M. W., Stearman, R. S., Thayer, T., West, J. D., & Yuan, J. X. (2019). Sorting Nexin 29 (SNX29) as a Novel Biomarker for Vasoresponsive Pulmonary Arterial Hypertension. In C26. LET IT BLEED: ENDOTHELIAL INJURY AND ANGIOGENESIS IN PULMONARY HYPERTENSION.

Presentations

• Karnes, J. H. (2024, June). Big Data and Diversity in Pharmacogenomic Discovery. University of Utah School of Medicine, Division of Health System Innovation and Research. Salt Lake City, Utah: University of Utah School of Medicine.
• Karnes, J. H. (2024, May). Precision Medicine and Diversity. Federal University of Sao Paulo and State University of Campinas (UNICAMP) Joint Seminar. Campinas, Brazil: Federal University of Sao Paulo and State University of Campinas (UNICAMP).
• Karnes, J. H. (2024, November). Phenome-Wide Association of APOE Alleles in the All of Us Research Program. 2024 American Society of Human Genetics Annual Meeting. Denver, CO: American Society of Human Genetics.
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  Selected for platform presentation
• Karnes, J. H. (2024, September). Opportunities for Discovery in Precision Medicine: Big Data and Diversity. Northwestern University Feinberg School of Medicine Department of Pharmacology Seminar Series. Chicago, IL: Northwestern University Feinberg School of Medicine.
• Karnes, J. H. (2023). From Big Data to Precision Medicine: Predicting, Preventing, and Understanding Adverse Drug Reactions. PHARM TALKR Ken Coit College of Pharmacy.
• Karnes, J. H. (2023). HLA Pharmacogenomics: Predicting, Preventing, and Understanding Adverse Drug Reactions. 2023 Western Medicaid Pharmacy Administrators Association Meeting. Tucson, AZ: Western Medicaid Pharmacy Administrators Association (WMPAA).
• Karnes, J. H. (2023). Heparin-Induced Thrombocytopenia: Potential for Precision Medicine. American Society of Hematology Precision Hematology Webinar Series. Virtual: American Society of Hematology.
• Karnes, J. H. (2023). Opportunities for Research in Precision Health: The All of Us Research Program . Family Medicine Grand RoundsUniversity of Arizona Department of Family Medicine.
• Karnes, J. H. (2023). Pharmacogenomics of Adverse Drug Reactions: Leveraging Electronic Health Records and the Importance of Research in Diverse Populations. University of Arizona College of Pharmacy National Advisory Board Meeting. Phoenix, AZ: University of Arizona College of Pharmacy.
• Karnes, J. H. (2023). The All of Us Research Program and the Transformative Potential of Diversity in Precision Medicine. Reimagine Health SymposiumUniversity of Arizona College of Medicine-Phoenix.
• Karnes, J. H. (2023, June). Overview and Updates for the All of Us Research Program. Pharmacogenomics Global Research Network Annual Meeting. Memphis, TN: Pharmacogenomics Global Research Network.
• Karnes, J. H. (2021, March). Big Drug Data: A Guide to Utilizing Electronic Health Records for Clinical Pharmacology Research. ASCPT Annual Meeting.
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  Co-Chaired, developed content for, and moderated session with three speakers.
• Karnes, J. H. (2020, February 2020). Cardiovascular Pharmacogenomics to Predict Adverse Drug Reactions: Focus on Heparin-Induced Thrombocytopenia. Sarver Heart Center Grand Rounds. Tucson, AZ: Sarver Heart Center.
• Karnes, J. H. (2020, September). Evidence for Implementation of PGx for Hypersensitivity Reactions and Future Directions. University of Minnesota Pharmacogenomics Conference 2020.
• Karnes, J. H. (2019, July). Precision Medicine in Diverse Populations: Improving Drug Safety and Efficacy while Minimizing Racial Disparities. University of Sydney School of Pharmacy Seminar. Sydney, New South Wales, Australia: University of Sydney School of Pharmacy.
• Karnes, J. H. (2019, March). Challenges and Solutions for Precision Medicine in Diverse Patient Populations. University of Florida Precision Medicine Conference. Orlando, FL: University of Florida.
• Karnes, J. H. (2019, March). Predicting Immune-Mediated Adverse Drug Reactions and Emerging Immunogenetic Discoveries” as part of a session, “. American Society for Clinical Pharmacology and Therapeutics Annual Meeting. Washington DC: American Society for Clinical Pharmacology and Therapeutics.
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  Organized session as co-chair and spoke as one of three workshop speakers for a marquis presentation "Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions"
• Karnes, J. H. (2019, September). Cardiovascular Pharmacogenomics to Predict Adverse Drug Reactions: Heparin-Induced Thrombocytopenia and Beyond. University of Tours Departmental Seminar. Tours, France: University of Tours.
• Karnes, J. H. (2018, June). Multiethnic Populations and Precision Medicine: Managing the Lack of Genetic Data and Clinical Studies. Pharmacogenomics Conference 2018 Genomic Testing to Individualize Drug Therapy. Minneapolis, MN: University of Minnesota.
• Karnes, J. H. (2018, March). Clinical and Translational Pharmacology of siRNA Therapeutics. ASCPT Annual Meeting. Orlando, FL: American Society for Clinical Pharmacology and Therapeutics.
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  Chaired workshop at ASCPT Annual Meeting
• Karnes, J. H. (2018, March). Unveiling the Genetic Architecture of Human Disease for Precision Medicine. ASCPT Annual Meeting. Orlando, FL: American Society for Clinical Pharmacology and Therapeutics.
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  Chaired workshop at ASCPT Annual Meeting
• Karnes, J. H. (2018, October). Discovering immunogenetic associations using electronic health records: heparin-induced thrombocytopenia and beyond. Genetics Graduate Interdisciplinary Program Seminar. Tucson, AZ: Genetics Graduate Interdisciplinary Program.
• Karnes, J. H. (2018, October). Pharmacogenomics in Cardiovascular Medicine: Minimizing Racial Disparities while Improving Drug Safety and Efficacy. Western Medicaid Pharmacy Administrators Association 2018 Annual Meeting. Tucson, AZ: Western Medicaid Pharmacy Administrators Association.
• Karnes, J. H. (2018, October). Translating Cardiovascular Genetics to Patient Care. 2018 Annual Meeting for the American Society of Human Genetics. San Diego, CA: American Society of Human Genetics.
• Karnes, J. H. (2018, September). Pharmacogenomics of Vasodilator Response in Pulmonary Arterial Hypertension. Pharmacogenomics Research Network (PGRN) Research In Progress Seminar (RIPS).
• Karnes, J. H. (2017, April). Cardiovascular Pharmacogenomics: Meeting the Unmet Clinical Needs. Precision Medicine Symposium. Tucson, AZ: Center for Applied Genetics and Genomic Medicine.
• Karnes, J. H. (2017, April). Genetic Determinants of Heparin-Induced Thrombocytopenia. PGRN-Riken Strategic Meeting. Yokohama, Japan: Riken Center for integrative Medical Sciences.
• Karnes, J. H. (2017, November). Tackling big data: Network systems analysis for high throughput data interpretation. AHA Scientific Sessions. Anaheim, CA: American Heart Association.
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  Moderated workshop for Genomic and Precision Medicine
• Karnes, J. H. (2016, January). Pharmacogenomics of Heparin-Induced Thrombocytopenia: Meeting the Unmet Clinical Needs. Pharmacology and Toxicology Departmental Seminar.
• Karnes, J. H. (2016, June). Unravelling Immunogenetic Phenotypes using Electronic Health Records Resources: Heparin-Induced Thrombocytopenia and Beyond. Department of Transfusion Medicine Seminar, Ernst-Moritz-Arndt-Universität, Greifswald, Germany. Greifswald, Germany: Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
• Karnes, J. H. (2016, November). Careers in Translational Research. UA College of Pharmacy Graduate Program Seminar.
• Karnes, J. H. (2016, September). Pharmacogenomics of Heparin-Induced Thrombocytopenia: Meeting the Unmet Clinical Needs. Department of Epidemiology and Biostatistics Clinical and Translational Research SeminarUniversity of Arizona.
• Karnes, J. H. (2015, APRIL). Association of HLA-DRB3*01:01 with Heparin-Induced Thrombocytopenia. Pharmacogenomics Research Network (PGRN) Spring Meeting. State College, PA: Pharmacogenomics Research Network (PGRN).
• Karnes, J. H. (2015, November). Pharmacogenomics of Heparin-Induced Thrombocytopenia: Meeting the Unmet Clinical Needs. Department of Pharmacotherapy and Translational Research Seminar. Gainesville, FL: University of Florida.
• Karnes, J. H. (2014, JANUARY). Pharmacogenomics of Heparin-Induced Thrombocytopenia. Grand Rounds, Vanderbilt University Division of Clinical Pharmacology.
• Karnes, J. H. (2014, JANUARY). Pharmacogenomics of Heparin-Induced Thrombocytopenia. Seminar - University of Southern California.
• Karnes, J. H. (2014, OCTOBER). Genome-wide association study of fluoroquinolone-induced tendonitis. Pharmacogenomics Practice Research Network Business Meeting and Networking ForumAmerican College of Clinical Pharmacy.
• Karnes, J. H. (2013, SEPTEMBER). Clinical Pharmacogenomics. 8th Clinical Pharmacy Week - Austrian Society of Clinical Pharmacy. VIENNA, AUSTRIA: Austrian Society of Clinical Pharmacy.
• Karnes, J. H. (2012, FEBRUARY). Long term antihypertensive exposure and adverse metabolic effects: PEAR Follow-up Study. UF Department of Pharmacotherapy and Translational Research SeminarUniversity of Florida College of Pharmacy.
• Karnes, J. H. (2011, FEBRUARY). Pharmacogenetic risk factors for thiazide-associated dysglycemia. UF Department of Pharmacotherapy and Translational Research SeminarUniversity of Florida College of Pharmacy.
• Karnes, J. H. (2010, MAY). New-Onset Diabetes Risk Associated with Antihypertensive Therapy Is Modified by a Single Nucleotide Polymorphism (SNP) in the L-Type Calcium Channel (LTCC) Alpha 1C Subunit Gene (CACNA1C). National Predoctoral Clinical Research Training Program Meeting.
• Karnes, J. H. (2009, OCTOBER). What is the Evidence Associating Antihypertensive-induced Diabetes with Adverse Outcomes?. UF Department of Pharmacotherapy and Translational Research SeminarUniversity of Florida College of Pharmacy.

Poster Presentations

• El Rouby, N., Marcatto, L., Claudio, K., Tavares, L., Steiner, H., Botton, M., Lubitz, S., Scott, S., Karnes, J. H., Cavallari, L. H., Santos, P., & Duconge, J. (2019, March 2019). Multi-Site Investigation of Pharmacogenetic Determinants of Warfarin Dose Variability in Latinos. American Society for Clinical Pharmacology and Therapeutics. Washington DC: American Society for Clinical Pharmacology and Therapeutics. Clinical Pharmacology & Therapeutics 2019, 105(S1), S119 (OIII-02).
• Karnes, J. H. (2019, November). Genetic admixture and survival in diverse populations with pulmonary arterial hypertension (PAH). American Heart Association Scientific Sessions. Philadelphia, PA: American Heart Association.
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  Karnes JH, Weiner HW, Schwantes-An TH, Natarajan B, Chaturvedi A, Arora A, Batai K, Nair V, Steiner HE, Giles JB, Yu J, Hosseini M, Pauciulo MW, Lutz KA, Coleman AW, Feldman J, Vanderpool R, Tang H, Garcia JGN, Yuan JXJY, Rischard F, Kittles R, Tiwari HK, Nichols WC, Benza R, Desai AA. Genetic admixture and survival in diverse populations with pulmonary arterial hypertension (PAH). American Heart Association Scientific Sessions, Philadelphia, PA, November 2019.
• Karnes, J. H., Thayer, T., Arora, A., Garcia, J. G., Batai, K., Halladay, S., Lutz, K., Coleman, A., Pauciulo, M., Kittles, R., Geraci, M. W., Yuan, J. X., West, J., Hemnes, A., Stearman, R., Nichols, W. C., Brittain, E., & Desai, A. (2019, May 2019). Sorting Nexin 29 (SNX29) as a novel biomarker for Vasoresponsive Pulmonary Arterial Hypertension. American Thoracic Society Annual Meeting. Dallas, TX: American Thoracic Society.
• Aljabri, A., Huckleberry, Y., Karnes, J. H., Gharaibeh, M., Kutbi, H., Raz, Y., Yun, S., Abraham, I., & Erstad, B. (2016, November). Cost-Effectiveness of Anticoagulants for the Management of Suspected Heparin-Induced Thrombocytopenia in the US. American Heart Association Scientific Sessions.
• Bastarache, L., Karnes, J. H., Shaffer, C., Gaudieri, S., Glazer, A., Steiner, H., Mosley, J., Mallal, S., Phillips, E., Denny, J., & Roden, d. (2016, October). Comparison of HLA Allelic Imputation Programs. American Society of Human Genetics Annual Meeting.
• Hemler, J. A., Marston, E., Karnes, J. H., Glazer, A., Denny, J., Phillips, E., Mallal, S., & Kendall, P. (2016, March). A Study of Immunogenetic Associations with Peanut Allergy utilizing a Novel DNA Repository. American Academy of Allergy, Asthma & Immunology (AAAAI). Los Angelos, CA.
• Karnes, J. H. (2018, May). Genetic Determinants of Risk and Survival in Pulmonary Arterial Hypertension.. American Thoracic Society Annual Meeting. San Diego: ATS.
• Karnes, J. H. (2018, November). Genetic Admixture and Clinical Profiles in Minority Populations with Pulmonary Arterial Hypertension. American Heart Association Scientific Sessions. Chicago, IL: AHA.
• Karnes, J. H. (2018, November). Genetic Determinants of Vasodilator Response in Pulmonary Arterial Hypertension. American Heart Association Scientific Sessions. Chicago, IL: AHA.
• Karnes, J. H., Bastarache, L., Shaffer, C., Gaudieri, S., Xu, Y., Glazer, A. M., Mosley, J., Raychaudhuri, S., Mallal, S., Ye, Z., Mayer, J., Brilliant, M., Hebbring, S., Roden, D., Phillips, E., & Roden, D. (2016, October). A Clinical Catalogue of Phenotypes Associated with Variation in the MHC Locus. American Society of Human Genetics Annual Meeting.
• Karnes, J. H., Phillips, E., Shaffer, C., Denny, J., Mosely, J., & Roden, D. (2016, October). HLA-KIR Interactions in Heparin-Induced Thrombocytopenia. American College of Clinical Pharmacy.
• Kaye, J., Schultz, L., Steiner, H., Kittles, R., Cavallari, L., & Karnes, J. H. (2016, November). Performance of warfarin pharmacogenetic dosing algorithms in United States minority groups.. American Indian Science and Engineering Society (AISES) National Conference. Minneapolis, MN.
• Karnes, J. H., Batai, K., Arora, A., Kaye, J., Steiner, H., Nair, V., Garcia, J. G., Yuan, J., Paucilio, M. W., Nichols, W. C., Kittles, R., & Desai, A. (2017, November). Genome-Wide Association Study of Vasodilator Response in Pulmonary Arterial Hypertension. American Heart Association Scientific Sessions. Anaheim, CA: AHA.
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  Late Breaking AbstractCirculation. 2017; 136: A24015
• Larriva, P. M., Campbell, P., Nix, D. E., Quinn, D., Klimecki, W., & Karnes, J. H. (2017, October). Efficacy of personal pharmacogenomic testing as an educational tool in the pharmacy curriculum. American College of Clinical Pharmacy Annual Meeting. Phoenix, AZ.
• Mosley, J., Feng, Q., Wells, Q. S., Van Driest, S., Shaffer, C., Edwards, T., Bastarache, L., Wei, W. Q., Davis, L. K., McCarty, C. A., Thompson, W., Chute, C. G., Gordon, A. S., Palmer, M. R., Crosslin, D. R., Larson, E. B., Carrell, D., Kullo, I. J., Pacheco, J. A., , Peissig, P., et al. (2017, October). Genetic predictors of biomarker levels derived from prospective epidemiologic cohorts applied to electronic health records to identify new biomarker-disease associations.. American Society of Human Genetics Annual Meeting. Orlando.
• Kaye, J., & Karnes, J. H. (2016, August). Literature review of performance of genotype-guided warfarin dosing algorithms in diverse ethnic groups. Association of American Indian Physicians (AAIP) 45th Annual Meeting. Oakland, CA.
• Karnes, J. H., Cronin, R. M., Shaffer, C. M., Mosley, J. D., Mallal, S., Phillips, E. J., & Roden, D. M. (2015, November). Association of HLA-DRB3*01:01 with Heparin-Induced Thrombocytopenia. American Heart Association.
• Karnes, J. H., Denny, J. C., Bowton, E. A., Shaffer, C. M., Mosley, J. D., Van Driest, S., Weeke, P. E., Wells, Q. S., & Roden, D. M. (2015, FEB). GENOME-WIDE ASSOCIATION STUDY OF PLATELET FACTOR 4/HEPARIN ANTIBODY FORMATION.. CLINICAL PHARMACOLOGY & THERAPEUTICS.
• Karnes, J. H., McDonough, C. W., Gong, Y., Langaee, T. Y., Pepine, C. J., Johnson, J. A., & Cooper-DeHoff, R. M. (2012, MAR). ALPHA ADDUCIN-1 (ADD1)SINGLENUCLEOTIDE POLYMORPHISM (SNP) ASSOCIATED WITH NEW ONSET DIABETES RISK WITH HYDROCHLOROTHIAZIDE (HCTZ) THERAPY IN THE INTERNATIONAL VERAPAMIL SR TRANDOLAPRIL GENETIC SUBSTUDY (INVEST-GENES). CLINICAL PHARMACOLOGY & THERAPEUTICS.
• KARNES, J. H., MOSLEY, J. D., SHAFFER, C. M., BOWTON, E. A., DELANEY, J. T., VAN DRIEST, S. L., WEEKE, P. E., WELLS, Q. S., & DENNY, J. C. (2014, OCTOBER). Genome-wide association study of fluoroquinolone-induced tendonitis. American College of Clinical Pharmacy Annual Meeting.
• Karnes, J. H., Denny, J. C., Cronin, R. M., Shaffer, C. M., Bowton, E. A., Cowan, J., Mosley, J. D., Van Driest, S. L., Weeke, P. E., Wells, Q. S., & Roden, D. M. (2014, November). Influence of Exonic Variation on Heparin-Induced Thrombocytopenia. American Heart Association Scientific Sessions.
• SANDERS, M., KARNES, J., DENNY, J., RODEN, D., IKIZLER, T., & BIRDWELL, K. (2014, JULY). The Use of a DNA Biobank Linked to Electronic Medical Records to Determine Clinical and Genetic Predictors of Cutaneous Squamous Cell Carcinoma in Kidney Transplant Recipients. World Transplant Congress.
• Wells, Q. S., Mosley, J. D., Van Driest, S. L., Weeke, P., Karnes, J. H., Shaffer, C. M., Bowton, E., Denny, J. C., & Roden, D. M. (2014, NOV 26). Genomwide-Association Identifies a Novel Locus for Anthracycline Cardiotoxicity. CIRCULATION.
• Gong, Y., Moore, M. J., Karnes, J. H., McDonough, C. W., Wang, Z., Langaee, T. Y., Beitelshees, A. L., Turner, S. T., Chapman, A. B., Gums, J. G., Bailey, K. R., Boerwinkle, E., Johnson, J. A., & Cooper-DeHoff, R. M. (2013, FEB). FASTING GLUCOSE LOCI ASSOCIATED WITH GLUCOSE RESPONSE TO ANTIHYPERTENSIVES- RESULTS FROM THE PHARMACOGENOMIC EVALUATION OF ANTIHYPERTENSIVE RESPONSES (PEAR) STUDY. CLINICAL PHARMACOLOGY & THERAPEUTICS.
• MOSLEY, J., SHAFFER, C., VAN DRIEST, S., WEEKE, P., WELLS, Q., KARNES, J., VELEZ-EDWARDS, D., WEI, W., TEIXEIRA, P., BASTARACHE, L., CRAWFORD, D., MANOLIO, T., BOTTINGER, E., MCCARTY, C., LINNEMAN, J., PACHECO, J., THOMPSON, W., CHISHOLM, R., JARVIK, G., , CROSSLIN, D., et al. (2013, October). A genome-wide association study identified variants in KCNIP4 associated with ACE inhibitor induced cough. American Society of Human Genetics Annual Meeting.
• MOSLEY, J., VAN DRIEST, S., LARKIN, E., WEEKE, P., WITTE, J., WELLS, Q., KARNES, J., GUO, Y., BASTARACHE, L., OLSON, L., MCCARTY, C., PACHECO, J., JARVIK, G., LARSON, E., CROSSLIN, D., KULLO, I., TROMP, G., KUIVANIEMI, H., CAREY, D., , RITCHIE, M., et al. (2013, OCTOBER). An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data. American Society of Human Genetics Annual Meeting.
• SANDERS, M., KARNES, J., DENNY, J., RODEN, D., IKIZLER, T., & BIRDWELL, K. (2013, NOVEMBER). Clinical and genetic predictors of cutaneous squamous cell carcinoma in kidney transplant recipients. American Society of Nephrology Kidney Week.
• WEEKE, P., MOSLEY, J., HANNA, D., SHAFFER, C., DELANEY, J., WELLS, Q., VAN DRIEST, S., KARNES, J., INGRAM, C., GUO, Y., SHYR, Y., NORRIS, K., KANNANKERIL, P., RAMIREZ, A., SMITH, J., MARDIS, E., NICKERSON, D., GEORGE, A., & RODEN, D. (2013, NOVEMBER). Exome Sequencing Implicates the Burden of Rare Potassium Channel Variants in the Risk of Drug Induced Long QT Syndrome. American Heart Association Scientific Sessions.
• Karnes, J. H., George, A. M., Gong, Y., Langaee, T. Y., Stauffer, L. A., Burkley, B. M., Pepine, C. J., Johnson, J. A., & Cooper-DeHoff, R. M. (2012, FEB). NEW-ONSET DIABETES RISK ASSOCIATED WITH ANTIHYPERTENSIVE THERAPY IN HYPERTENSIVE CORONARY ARTERY DISEASE PATIENTS IS MODIFIED BY A SINGLE NUCLEOTIDE POLYMORPHISM (SNP) IN THE L-TYPE CALCIUM CHANNEL (LTCC). CLINICAL PHARMACOLOGY & THERAPEUTICS.
• Karnes, J. H., Vo, T. T., Gong, Y., Langaee, T. Y., Beitelshees, A. L., Turner, S. T., Chapman, A. B., Gums, J. G., Bailey, K., Boerwinkle, E., Pepine, C. J., Johnson, J. A., & Cooper-DeHoff, R. M. (2011, FEB). KCNJ1 SNPS ARE ASSOCIATED WITH INCREASED FASTING GLUCOSE AND RISK OF NEW ONSET DIABETES DURING HCTZ THERAPY. CLINICAL PHARMACOLOGY & THERAPEUTICS.
• Johnson, J., Karnes, J., Brunner, M., Gong, Y., Langaee, T., Cooper-Dehoff, R., & Pepine, C. (2010, FEB). Lack of association of the angiotensin II type I receptor (AGTR1) 1166A > C polymorphism with cardiovascular and cerebrovascular outcomes in a subgroup of patients of the international verapamil SR/trandolaprtl study (INVEST).. CLINICAL PHARMACOLOGY & THERAPEUTICS.
• Brunner, M., Karnes, J., Gong, Y., Langaee, T., Copper-DeHoff, R., Pepine, C., & Johnson, J. (2006, FEB). Association of angiotensin II type 1 receptor (AGTR1) 1166A > C polymorphism with blood pressure response to ACE inhibitor in a subgroup of patients of the international verapamil SR/trandolapril study (INVEST).. CLINICAL PHARMACOLOGY & THERAPEUTICS.