Xingnan Li
- Associate Professor, Medicine - (Research Scholar Track)
Contact
- (520) 626-2905
- Bioscience Research Labs, Rm. 251
- Tucson, AZ 85721
- lixingnan1@deptofmed.arizona.edu
Biography
The current focus of my research is to understand the role of genetics and phenotypes in common respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD).
Degrees
- M.S. Statistics and Probability
- Michigan State University, East Lansing, Michigan, United States
- Ph.D. Genetics
- Michigan State University, East Lansing, Michigan, United States
- Studies of GATA-3 transcription factor as a positional candidate gene for a murine model of asthma
- B.S. Biochemistry and Molecular Biology
- Peking University, Beijing, China
Work Experience
- Department of Medicine (2019 - Ongoing)
- Department of Medicine, University of Arizona (2017 - 2019)
- Wake Forest School of Medicine (2010 - 2016)
- Wake Forest School of Medicine (2006 - 2010)
Awards
- ATS Scientific Abstract Award
- American Thoracic Society, Spring 2015
- American Thoracic Society, Spring 2014
- David Bates Awards
- American Thoracic Society EOPH Assembly, Spring 2015
- Allan de Weck Travel Grant
- Collegium Internationale Allergologicum, Fall 2012
- World Allergy Congress Travel Award
- World Allergy Congress, Winter 2011
- ATS General Travel Award
- American Thoracic Society AII Assembly, Spring 2010
Licensure & Certification
- SAS Advance Programming Certificate, SAS (2006)
- SAS Base Programming Certificate, SAS (2006)
Interests
Research
My overall research goal is to extend the work on asthma and COPD to other common diseases and to analysis of omics data (genomics, transcriptomics, proteomics, and epigenomics).
Teaching
Statistical genetics; genetic data analysis
Courses
2022-23 Courses
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Found Med Gen
CMM 620 (Spring 2023)
2021-22 Courses
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Found Med Gen
CMM 620 (Spring 2022)
2020-21 Courses
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Found Med Gen
CMM 620 (Spring 2021)
2019-20 Courses
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Found Med Gen
CMM 620 (Spring 2020)
Scholarly Contributions
Chapters
- Slager, R. E., Li, X., Meyers, D. A., Bleecker, E. R., & Li, X. (2014). Genetics and Asthma. In Clinical Asthma: Theory and Practice. CRC Press. doi:10.1201/B16468-3
- Slager, R. E., Li, X., Meyers, D. A., Bleecker, E. R., & Li, X. (2011). Recent developments in the genetics of asthma susceptibility and severity. In European Respiratory Monograph (Number 51): Difficult-to-Treat Severe Asthma. European Respiratory Society. doi:10.1183/1025448X.10001010
Journals/Publications
- Bleecker, E. R., Meyers, D. A., Billheimer, D., Li, H., Newbold, P., Kwiatek, J., Hirsch, I., Katial, R., & Li, X. (2023). Clinical Implications of Longitudinal Blood Eosinophil Counts in Patients With Severe Asthma. The journal of allergy and clinical immunology. In practice, 11(6), 1805-1813.More infoThe stability and variability of blood eosinophil counts (BECs) to phenotype patients with severe asthma is not fully understood.
- Hoof, I., Bønnelykke, K., Stranzl, T., Brand, S., Li, X., Shamji, M. H., Meyers, D. A., Bateman, E. D., Bleecker, E., & Andersen, P. S. (2023). Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma. Thorax.More infoHypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).
- Iannuzo, N., Welfley, H., Li, N. C., Johnson, M. D., Rojas-Quintero, J., Polverino, F., Guerra, S., Li, X., Cusanovich, D. A., Langlais, P. R., & Ledford, J. G. (2023). CC16 drives VLA-2-dependent SPLUNC1 expression. Frontiers in immunology, 14, 1277582.More infoCC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated.
- Izquierdo, M., Marion, C. R., Genese, F., Newell, J. D., O'Neal, W. K., Li, X., Hawkins, G. A., Barjaktarevic, I., Barr, R. G., Christenson, S., Cooper, C. B., Couper, D., Curtis, J., Han, M. K., Hansel, N. N., Kanner, R. E., Martinez, F. J., Paine, R., Tejwani, V., , Woodruff, P. G., et al. (2023). Impact of Bronchiectasis on COPD Severity and Alpha-1 Antitrypsin Deficiency as a Risk Factor in Individuals with a Heavy Smoking History. Chronic obstructive pulmonary diseases (Miami, Fla.), 10(3), 199-210.More infoBronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals.
- Li, H., & Li, X. (2023). Genetic relationships between high blood eosinophil count, asthma susceptibility, and asthma severity. The Journal of asthma : official journal of the Association for the Care of Asthma, 1-13.More infoGenetic relationships between blood eosinophil count (BEC), asthma susceptibility, and severity are unclear. We sought to identify the genetic difference between type 2 (T2) and nontype 2 (non-T2) asthma (defined by BEC) and investigate genetic relationships between high BEC, asthma susceptibility, and severity.
- Li, H., Castro, M., Denlinger, L. C., Erzurum, S. C., Fahy, J. V., Gaston, B., Israel, E., Jarjour, N. N., Levy, B. D., Mauger, D. T., Moore, W. C., Wenzel, S. E., Zein, J., Bleecker, E. R., Meyers, D. A., Chen, Y., Li, X., & , N. S. (2023). Investigations of a combination of atopic status and age of asthma onset identify asthma subphenotypes. The Journal of asthma : official journal of the Association for the Care of Asthma, 60(10), 1843-1852.More infoSubphenotypes of asthma may be determined by age onset and atopic status. We sought to characterize early or late onset atopic asthma with fungal or non-fungal sensitization (AAFS or AANFS) and non-atopic asthma (NAA) in children and adults in the Severe Asthma Research Program (SARP). SARP is an ongoing project involving well-phenotyped patients with mild to severe asthma.
- Li, X., Guerra, S., Ledford, J. G., Kraft, M., Li, H., Hastie, A. T., Castro, M., Denlinger, L. C., Erzurum, S. C., Fahy, J. V., Gaston, B., Israel, E., Jarjour, N. N., Levy, B. D., Mauger, D. T., Moore, W. C., Zein, J., Kaminski, N., Wenzel, S. E., , Woodruff, P. G., et al. (2023). Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity. American journal of respiratory and critical care medicine, 207(4), 438-451.More infoCC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (, , , , , and ) and positively correlated with expression levels of Th1 and inflammation genes ( and ). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.
- Li, X., Li, H., Christenson, S. A., Castro, M., Denlinger, L. C., Erzurum, S. C., Fahy, J. V., Gaston, B. M., Israel, E., Jarjour, N. N., Levy, B. D., Mauger, D. T., Moore, W. C., Zein, J., Kaminski, N., Wenzel, S. E., Woodruff, P. G., Bleecker, E. R., Meyers, D. A., & , N. S. (2023). Genetic analyses of chr11p15.5 region identify - associated with asthma-related phenotypes. The Journal of asthma : official journal of the Association for the Care of Asthma, 60(10), 1824-1835.More infoGenome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP).
- Weinstock, J. S., Laurie, C. A., Broome, J. G., Taylor, K. D., Guo, X., Shuldiner, A. R., O'Connell, J. R., Lewis, J. P., Boerwinkle, E., Barnes, K. C., Chami, N., Kenny, E. E., Loos, R. J., Fornage, M., Redline, S., Cade, B. E., Gilliland, F. D., Chen, Z., Gauderman, W. J., , Kumar, R., et al. (2023). The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. Science advances, 9(17), eabm4945.More infoNononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
- Hu, X., Qiao, D., Kim, W., Moll, M., Balte, P. P., Lange, L. A., Bartz, T. M., Kumar, R., Li, X., Yu, B., Cade, B. E., Laurie, C. A., Sofer, T., Ruczinski, I., Nickerson, D. A., Muzny, D. M., Metcalf, G. A., Doddapaneni, H., Gabriel, S., , Gupta, N., et al. (2022). Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. American journal of human genetics, 109(5), 857-870.More infoWhile polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p
- John, C., Guyatt, A. L., Shrine, N., Packer, R., Olafsdottir, T. A., Liu, J., Hayden, L. P., Chu, S. H., Koskela, J. T., Luan, J., Li, X., Terzikhan, N., Xu, H., Bartz, T. M., Petersen, H., Leng, S., Belinsky, S. A., Cepelis, A., Hernández Cordero, A. I., , Obeidat, M., et al. (2022). Genetic Associations and Architecture of Asthma-COPD Overlap. Chest, 161(5), 1155-1166.More infoSome people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.
- Kho, A. T., McGeachie, M. J., Li, J., Chase, R. P., Amr, S. S., Hastie, A. T., Hawkins, G. A., Li, X., Chupp, G. L., Meyers, D. A., Bleecker, E. R., Weiss, S. T., & Tantisira, K. G. (2022). Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma. Thorax, 77(5), 452-460.More infoAsthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies.
- Bleecker, E. R., Woodruff, P. G., Wenzel, S. E., Moore, W. C., Modena, B. D., Meyers, D. A., Li, X., Li, H., Levy, B. D., Kaminski, N., Jarjour, N. N., Israel, E., Hastie, A. T., Gaston, B., Fahy, J. V., Erzurum, S. C., Denlinger, L. C., Christenson, S. A., Castro, M., , Busse, W. W., et al. (2021). Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.. The Journal of allergy and clinical immunology, 147(3), 894-909. doi:10.1016/j.jaci.2020.07.030More infoThe Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium..We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program..Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed..Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10-9
- Daya, M., Cox, C., Acevedo, N., Boorgula, M. P., Campbell, M., Chavan, S., Cho, M. H., David, G. L., Kachroo, P., Lasky-Su, J., Li, X., McHugh, C. P., Qiao, D., Rafaels, N., Beck, L. A., Bleecker, E. R., Caraballo, L., Cupples, A. L., Figueiredo, C. A., , Gallo, R. L., et al. (2021). Multiethnic genome-wide and HLA association study of total serum IgE level. The Journal of allergy and clinical immunology, 148(6), 1589-1595.More infoTotal serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.
- Dy, A. B., Langlais, P. R., Barker, N. K., Addison, K. J., Tanyaratsrisakul, S., Boitano, S., Christenson, S. A., Kraft, M., Meyers, D., Bleecker, E. R., Li, X., & Ledford, J. G. (2021). Myeloid-associated differentiation marker is a novel SP-A-associated transmembrane protein whose expression on airway epithelial cells correlates with asthma severity. Scientific reports, 11(1), 23392.More infoSurfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. Previous studies from our group have shown that SP-A mediates eosinophil activities, including degranulation and apoptosis. In order to identify potential binding partners on eosinophils for SP-A, eosinophil lysates were subjected to SP-A pull-down and tandem mass spectrometry (MS/MS) analysis. We identified one membrane-bound protein, myeloid-associated differentiation marker (MYADM), as a candidate SP-A binding partner. Blocking MYADM on mouse and human eosinophils ex vivo prevented SP-A from inducing apoptosis; blocking MYADM in vivo led to increased persistence of eosinophilia and airway hyper-responsiveness in an ovalbumin (OVA) allergy model and increased airways resistance and mucus production in a house dust mite (HDM) asthma model. Examination of a subset of participants in the Severe Asthma Research Program (SARP) cohort revealed a significant association between epithelial expression of MYADM in asthma patients and parameters of airway inflammation, including: peripheral blood eosinophilia, exhaled nitric oxide (FeNO) and the number of exacerbations in the past 12 months. Taken together, our studies provide the first evidence of MYADM as a novel SP-A-associated protein that is necessary for SP-A to induce eosinophil apoptosis and we bring to light the potential importance of this previously unrecognized transmembrane protein in patients with asthma.
- Kasela, S., Ortega, V. E., Martorella, M., Garudadri, S., Nguyen, J., Ampleford, E., Pasanen, A., Nerella, S., Buschur, K. L., Barjaktarevic, I. Z., Barr, R. G., Bleecker, E. R., Bowler, R. P., Comellas, A. P., Cooper, C. B., Couper, D. J., Criner, G. J., Curtis, J. L., Han, M. K., , Hansel, N. N., et al. (2021). Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. Genome medicine, 13(1), 66.More infoThe large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.
- Lakshman Kumar, P., Wilson, A. C., Rocco, A., Cho, M. H., Wan, E., Hobbs, B. D., Washko, G. R., Ortega, V. E., Christenson, S. A., Li, X., Wells, J. M., Bhatt, S. P., DeMeo, D. L., Lutz, S. M., Rossiter, H., Casaburi, R., Rennard, S. I., Lomas, D. A., Labaki, W. W., , Tal-Singer, R., et al. (2021). Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease. Journal of cachexia, sarcopenia and muscle, 12(6), 1803-1817.More infoChronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.
- Bleecker, E. R., Wenzel, S. E., Moore, W. C., Meyers, D. A., Li, X., Li, H., Levy, B. D., Jarjour, N. N., Israel, E., Gaston, B., Fahy, J. V., Erzurum, S. C., Castro, M., Busse, W. W., & Bleecker, E. R. (2020). Longitudinal characteristics of the Severe Asthma Research Program (SARP) clinical clusters. European Respiratory Journal, 56. doi:10.1183/13993003.congress-2020.5038More infoBackground: Five clinical clusters (early-onset increasing severity clusters 1, 2, and 4, late-onset severe cluster 3, and late-onset severe obstructed cluster 5) have been identified in the SARP cross-sectional cohort (n=726; Moore 2010). This approach demonstrated asthma heterogeneity and showed differential responses to biologic therapy (Bleecker 2019 ERS). Objective: Investigate longitudinal phenotypes of clinical clusters in the SARP longitudinal cohort. Methods: Subjects in longitudinal cohort (n=594) with 3-year (n=461) and 5-year (n=272) were assigned to clinical clusters using an 11-variable discriminant function. Phenotypes were compared using Kruskal-Wallis test. Results: Baseline clinical characteristics of five clusters in the longitudinal cohort were similar to the cross-sectional cohort. From baseline to Year 5, 2/3 of subjects remained in the same cluster and 1/6 each changed to more severe or milder clusters. Cluster 5 had consistently higher numbers of asthma exacerbations than clusters 1-4. Responses to a corticosteroid evoked phenotype (before and after 40 mg intramuscular triamcinolone): severe asthma clusters 3-5 had greater % increase in FEV1 than non-severe clusters (p Conclusions: SARP clinical clusters are reproducible in the longitudinal cohort. Severe clusters have better responses to corticosteroid. Cluster 5 has consistently greater asthma exacerbations over time. Longitudinal changes in FEV1 primarily determine cluster progression.
- Bleecker, E. R., Woodruff, P. G., Wise, R. A., Wells, J. M., Tashkin, D. P., Rennard, S. I., Raman, S., Putcha, N., Pirozzi, C. S., Peters, S. P., Paulin, L., Paine, R., Ortega, V. E., Oelsner, E. C., O'neal, W. K., Moore, W. C., Meyers, D. A., Martinez, F. J., Li, X., , Lazarus, S. C., et al. (2020). The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.. American journal of respiratory and critical care medicine, 201(5), 540-554. doi:10.1164/rccm.201904-0769ocMore infoRationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.
- Li, X., Christenson, S. A., Modena, B., Li, H., Busse, W. W., Castro, M., Denlinger, L. C., Erzurum, S. C., Fahy, J. V., Gaston, B., Hastie, A. T., Israel, E., Jarjour, N. N., Levy, B. D., Moore, W. C., Woodruff, P. G., Kaminski, N., Wenzel, S. E., Bleecker, E. R., , Meyers, D. A., et al. (2020). Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways. The Journal of allergy and clinical immunology.More infoThe Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.
- Moll, M., Sakornsakolpat, P., Shrine, N., Hobbs, B. D., DeMeo, D. L., John, C., Guyatt, A. L., McGeachie, M. J., Gharib, S. A., Obeidat, M., Lahousse, L., Wijnant, S. R., Brusselle, G., Meyers, D. A., Bleecker, E. R., Li, X., Tal-Singer, R., Manichaikul, A., Rich, S. S., , Won, S., et al. (2020). Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. The Lancet. Respiratory medicine, 8(7), 696-708.More infoGenetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.
- Nielsen, J. B., Rom, O., Surakka, I., Graham, S. E., Zhou, W., Roychowdhury, T., Fritsche, L. G., Gagliano Taliun, S. A., Sidore, C., Liu, Y., Gabrielsen, M. E., Skogholt, A. H., Wolford, B., Overton, W., Zhao, Y., Chen, J., Zhang, H., Hornsby, W. E., Acheampong, A., , Grooms, A., et al. (2020). Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nature communications, 11(1), 6417.More infoPharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
- Thorleifsson, G., Olafsdottir, T. A., Bleecker, E. R., Xu, H., Wu, A. C., Wain, L. V., Tobin, M. D., Thorleifsson, G., Tesfaigzi, Y., Terzikhan, N., Stefansson, K., Shrine, N., Sayers, I., Sakoda, L. C., Ripatti, S., Petersen, H., Ortega, V. E., Olafsdottir, T., Meyers, D. A., , Luan, J., et al. (2020). A genome-wide association study of asthma-COPD overlap syndrome (ACOS). European Respiratory Journal, 56. doi:10.1183/13993003.congress-2020.4919More infoIndividuals with characteristics of both asthma and COPD (asthma-COPD overlap syndrome, ACOS) experience significantly worse outcomes than those with asthma or COPD alone. Despite hundreds of genetic associations with asthma, COPD and lung function, no genetic variants have specifically been associated with ACOS. We hypothesized that there are genetic determinants of ACOS and sought to identify these in a genome-wide association study. We defined ACOS based on self-reported doctor-diagnosed asthma and spirometric GOLD2+ airflow limitation. We tested 7693381 genetic variants for association with ACOS in 8068 cases and 40360 healthy controls from UK Biobank (stage 1). We identified signals where P Thirty-one genetic variants met criteria for inclusion in stage 2. Of these, eight were associated at genome-wide significance (P Whilst our results suggest that many genetic variants associated with ACOS are shared with asthma and/or COPD, we identify a new, distinct signal that may implicate cellular pathways characteristic of ACOS.
- Bleecker, E. R., Zangrilli, J., Newbold, P., Meyers, D. A., Li, X., Li, H., Hirsch, I., Goldman, M., & Bleecker, E. R. (2019). Benralizumab treatment and SARP cluster analysis. European Respiratory Journal, 54. doi:10.1183/13993003.congress-2019.pa1659More infoBackground: Severe asthma is heterogeneous, with different phenotypes and endotypes. Aims and Objectives: We identified subsets of benralizumab-treated patients (pts) with severe asthma by assignment to Severe Asthma Research Program (SARP) clinical clusters. Methods: Pts (N=2,281) from SIROCCO (Lancet 2016:2115; n=1,082) and CALIMA (Lancet 2016:2128; n=1,199) were assigned to clusters via a discriminant function based on 11 predictors. Drug responses were compared with the Kruskal-Wallis test (nominal p-values). Results: Pts met criteria for 4 of 5 SARP clusters. Cluster 2 pts (n=393) were 81% atopic with early onset moderate asthma (mean age 15 yrs). Cluster 4 pts (n=386) were 82% atopic with early onset severe asthma (mean age 11 yrs). Cluster 3 pts (n=641) were 50% atopic with late-onset severe asthma (mean age 47 yrs). Cluster 5 pts (n=861) were 55% atopic with late-onset asthma (mean age 33 yrs) and persistent airflow obstruction. All clusters had annual exacerbation rate reductions for combined benralizumab arms vs. placebo, which were greater in late-onset asthma clusters (Cluster 3, −48%; 5, −50%; p Conclusions: Benralizumab improved lung function and reduced exacerbations in all clusters, with greater effects in late-onset asthma Clusters 3 and 5 vs. early onset Clusters 2 and 4. This supports the importance of understanding asthma heterogeneity and responsiveness to targeted therapies.
- Li, X. (2019). Hot Topic: Precision Medicine for Asthma-Has the Time Come?. Current allergy and asthma reports, 19(10), 45.More infoAsthma is a common inflammatory airway disease, which affects more than 300 million people worldwide. Although conventional drugs are effective for most of the patients with mild-to-moderate asthma, they are less effective for patients with difficult-to-treat or severe asthma. Identification of asthma endotypes and biomarkers will lead to more precise approaches to treat asthma.
- Li, X., Hastie, A. T., Peters, M. C., Hawkins, G. A., Phipatanakul, W., Li, H., Moore, W. C., Busse, W. W., Castro, M., Erzurum, S. C., Gaston, B., Israel, E., Jarjour, N. N., Levy, B. D., Wenzel, S. E., Meyers, D. A., Fahy, J. V., Bleecker, E. R., & , N. H. (2019). Investigation of the relationship between IL-6 and type 2 biomarkers in patients with severe asthma. The Journal of allergy and clinical immunology.
- Ortega, V. E., Li, X., O'Neal, W. K., Lackey, L., Ampleford, E., Hawkins, G. A., Grayeski, P. J., Laederach, A., Barjaktarevic, I., Barr, R. G., Cooper, C., Couper, D., Han, M. K., Kanner, R. E., Kleerup, E. C., Martinez, F. J., Paine Iii, R., Peters, S. P., Pirozzi, C., , Rennard, S. I., et al. (2019). The Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS. American journal of respiratory and critical care medicine.More infoThe role of PI type Z heterozygotes and additional, rare variant genotypes in the gene encoding α1-antitrypsin (SERPINA1) in determining the COPD risk and severity is controversial.
- Sakornsakolpat, P., Prokopenko, D., Lamontagne, M., Reeve, N. F., Guyatt, A. L., Jackson, V. E., Shrine, N., Qiao, D., Bartz, T. M., Kim, D. K., Lee, M. K., Latourelle, J. C., Li, X., Morrow, J. D., Obeidat, M., Wyss, A. B., Bakke, P., Barr, R. G., Beaty, T. H., , Belinsky, S. A., et al. (2019). Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nature genetics, 51(3), 494-505.More infoChronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
- Schaefer, N., Li, X., Seibold, M. A., Jarjour, N. N., Denlinger, L. C., Castro, M., Coverstone, A. M., Teague, W. G., Boomer, J., Bleecker, E. R., Meyers, D. A., Moore, W. C., Hawkins, G. A., Fahy, J., Phillips, B. R., Mauger, D. T., Dakhama, A., Gellatly, S., Pavelka, N., , Berman, R., et al. (2019). The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium. JCI insight, 4(8).More infoBacterial permeability family member A1 (BPIFA1), also known as short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is a protein involved in the antiinflammatory response. The goal of this study was to determine whether BPIFA1 expression in asthmatic airways is regulated by genetic variations, altering epithelial responses to type 2 cytokines (e.g., IL-13). Nasal epithelial cells from patients with mild to severe asthma were collected from the National Heart, Lung, and Blood Institute Severe Asthma Research Program centers, genotyped for rs750064, and measured for BPIFA1. To determine the function of rs750064, cells were cultured at air-liquid interface and treated with IL-13 with or without recombinant human BPIFA1 (rhBPIFA1). Noncultured nasal cells with the rs750064 CC genotype had significantly less BPIFA1 mRNA expression than the CT and TT genotypes. Cultured CC versus CT and TT cells without stimulation maintained less BPIFA1 expression. With IL-13 treatment, CC genotype cells secreted more eotaxin-3 than CT and TT genotype cells. Also, rhBPIFA1 reduced IL-13-mediated eotaxin-3. BPIFA1 mRNA levels negatively correlated with serum IgE and fractional exhaled nitric oxide. Baseline FEV1% levels were lower in the asthma patients with the CC genotype (n = 1,016). Our data suggest that less BPIFA1 in asthma patients with the CC allele may predispose them to greater eosinophilic inflammation, which could be attenuated by rhBPIFA1 protein therapy.
- Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A., Batini, C., Fawcett, K. A., Song, K., Sakornsakolpat, P., Li, X., Boxall, R., Reeve, N. F., Obeidat, M., Zhao, J. H., Wielscher, M., , U. S., Weiss, S., Kentistou, K. A., , Cook, J. P., et al. (2019). Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nature genetics, 51(6), 1067.More infoAn amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A., Batini, C., Fawcett, K. A., Song, K., Sakornsakolpat, P., Li, X., Boxall, R., Reeve, N. F., Obeidat, M., Zhao, J. H., Wielscher, M., Weiss, S., Kentistou, K. A., Cook, J. P., , Sun, B. B., et al. (2019). New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nature genetics, 51(3), 481-493.More infoReduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
- Guerra, S., Bleecker, E. R., Woodruff, P. G., Paine, R., O'neal, W. K., Meyers, D. A., Martinez, F. J., Li, X., Li, H., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Hansel, N. N., Han, M. K., Guerra, S., Dransfield, M. T., Couper, D. J., Cooper, C. B., Christenson, S. A., , Bleecker, E. R., et al. (2018). Genomic analysis of CC16 as a biomarker for COPD. European Respiratory Journal, 52. doi:10.1183/13993003.congress-2018.pa1273More infoBackground: CC16 is a protein produced by bronchial epithelial cells (BEC) that participates in host defense. Objectives: Our purpose is to investigate CC16 as a biomarker for COPD using systems biology in the SPIROMICS cohort. Methods: Genome-wide pQTL analyses of CC16 serum protein levels were performed in non-Hispanic Whites (n=1,874) and African Americans (n=403). Spearman correlation analyses between CC16 mRNA levels and other protein-coding genes (n=14,746) were performed using RNAseq data from BEC (n=131). Association analyses between CC16 SNPs/mRNA/protein and COPD-related phenotypes were performed using a generalized linear model. Results: The A allele of rs3741240 was associated with lower CC16 protein levels in non-Hispanic Whites (p=9x10-6) and African Americans (p=0.04). CC16 mRNA levels were positively correlated with CC16 protein levels (p=0.02). CC16 mRNA levels were positively correlated with MUC5B, IL12A, C3, TLR5, IL6, DPP4, and SFTPD, and negatively correlated with MUC5AC, IL18R1, and TLR6 at genome-wide significant level (p 1 vs. 0, OR=0.8, p=0.02). Conclusions: rs3741240 is a pQTL SNP for CC16 protein levels. CC16 mRNA levels are positively correlated with inflammation genes and negatively correlated with atopic genes. These findings are consistent with eQTL and co-expression analyses from SARP asthma cohort (n=107) (Li, 2018, ATS abstract). CC16 protein levels were associated with reduced future COPD exacerbations and will be further investigated longitudinally in SPIROMICS.
- Li, X., Ortega, V. E., Ampleford, E. J., Graham Barr, R., Christenson, S. A., Cooper, C. B., Couper, D., Dransfield, M. T., Han, M. L., Hansel, N. N., Hoffman, E. A., Kanner, R. E., Kleerup, E. C., Martinez, F. J., Paine, R., Woodruff, P. G., Hawkins, G. A., Bleecker, E. R., Meyers, D. A., & , S. R. (2018). Genome-wide association study of lung function and clinical implication in heavy smokers. BMC medical genetics, 19(1), 134.More infoThe aim of this study is to identify genetic loci associated with post-bronchodilator FEV/FVC and FEV, and develop a multi-gene predictive model for lung function in COPD.
- Waage, J., Standl, M., Curtin, J. A., Jessen, L. E., Thorsen, J., Tian, C., Schoettler, N., , 2. R., , A. c., Flores, C., Abdellaoui, A., Ahluwalia, T. S., Alves, A. C., Amaral, A. F., Antó, J. M., Arnold, A., Barreto-Luis, A., Baurecht, H., van Beijsterveldt, C. E., , Bleecker, E. R., et al. (2018). Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis. Nature genetics, 50(9), 1343.More infoIn the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
- Waage, J., Standl, M., Curtin, J. A., Jessen, L. E., Thorsen, J., Tian, C., Schoettler, N., , 2. R., , A. c., Flores, C., Abdellaoui, A., Ahluwalia, T. S., Alves, A. C., Amaral, A. F., Antó, J. M., Arnold, A., Barreto-Luis, A., Baurecht, H., van Beijsterveldt, C. E., , Bleecker, E. R., et al. (2018). Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis. Nature genetics, 50(8), 1072-1080.More infoAllergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
- Bradford, E., Jacobson, S., Varasteh, J., Comellas, A. P., Woodruff, P., O'Neal, W., DeMeo, D. L., Li, X., Kim, V., Cho, M., Castaldi, P. J., Hersh, C., Silverman, E. K., Crapo, J. D., Kechris, K., & Bowler, R. P. (2017). The value of blood cytokines and chemokines in assessing COPD. Respiratory research, 18(1), 180.More infoBlood biomarkers are increasingly used to stratify high risk chronic obstructive pulmonary disease (COPD) patients; however, there are fewer studies that have investigated multiple biomarkers and replicated in multiple large well-characterized cohorts of susceptible current and former smokers.
- Hastie, A. T., Martinez, F. J., Curtis, J. L., Doerschuk, C. M., Hansel, N. N., Christenson, S., Putcha, N., Ortega, V. E., Li, X., Barr, R. G., Carretta, E. E., Couper, D. J., Cooper, C. B., Hoffman, E. A., Kanner, R. E., Kleerup, E., O'Neal, W. K., Paine, R., Peters, S. P., , Alexis, N. E., et al. (2017). Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort. The Lancet. Respiratory medicine, 5(12), 956-967.More infoIncreased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils.
- Bleecker, E. R., Woodruff, P. G., Ortega, V. E., Meyers, D. A., Martinez, F. J., Li, X., Li, H., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Han, M. K., Dransfield, M. T., Couper, D. J., Bleecker, E. R., & Barr, G. (2016). LATE-BREAKING ABSTRACT: Clinical characteristics of four endophenotypic clusters of smokers with preserved lung function. European Respiratory Journal, 48. doi:10.1183/13993003.congress-2016.pa4243More infoBackground: Smokers has been clustered into COPD and non-COPD clusters (Li, ATS 2016). Smokers with preserved lung function may have COPD symptoms, exacerbations, and usage of respiratory medicine (Woodruff, NEJM 2016, 374:1811-21). Objectives: We aim to compare clinical characteristics of four clusters mainly composed of smokers with preserved lung function. Methods: Clinical characteristics were compared using the Kruskal-Wallis test and chi-square test. Results: C1 consists of resistant smokers with normal lung function, early emphysema, lower HCU and inhaled steroid (ICS) use, and lower symptom scores. C2 consists of heavy smokers with normal lung function, early emphysema, higher HCU and ICS use, and higher blood neutrophils. C3 has normal lung function, no emphysema, and lower HCU and ICS use. C4 has lower lung function, no emphysema, higher HCU and ICS use, higher “label” of asthma, higher inflammation, and higher symptom scores. Conclusions: Four distinct endophenotypic clusters mainly composed of smokers with preserved lung function have been identified. This study supports heterogeneity of smokers and indicates the distinction between smokers with preserved lung function and COPD is not as simple as measuring spirometry alone .
- Bleecker, E. R., Woodruff, P. G., Rennard, S. I., Peters, S. P., Ortega, V. E., O'neal, W. K., Meyers, D. A., Martinez, F. J., Li, X., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Han, M. K., Couper, D. J., Bleecker, E. R., & Barr, R. G. (2016). LATE-BREAKING ABSTRACT: Effects of rareSERPINA1variants on emphysema and airtrapping in SPIROMICS. European Respiratory Journal, 48. doi:10.1183/13993003.congress-2016.pa1214More infoBackground: PI type Z heterozygotes (Glu 366 Lys in SERPINA1 ) with a prior smoking history have been shown to have greater CT scan-based emphysema compared to PI MM wild types (Sorheim CHEST 2010). There are no studies evaluating the regional effects of rare SERPINA1 variants on CT scan-based emphysema or airtrapping. Aims and Objectives: The effects of rare SERPINA1 variants on regional CT scan emphysema and airtrapping were evaluated in NHLBI SPIROMICS. Methods: 1,715 non-Hispanic Whites(NHW), 392 African Americans, and 98 Hispanics with ≥20 pack-year smoking were genotyped for 24 rare coding variants (allele frequency≤5%). Regression-based models of CT scan emphysema (%lung area≤-950 HFU) and airtrapping (%≤-856 HFU) were performed. Results: In NHW, PI Z was associated with bilateral emphysema (CC=7.8%, CT=12%, TT=24%, p =5.5x10 -8 ) and airtrapping (CC=25%, CT=34%, TT=54%, p =7.1x10 -9 ). PI Z heterozygotes (MZ, N=73), PI Z homozygotes (ZZ, N=9), and PI Z-containing compound heterozygotes (ZS/ZV R , N=7) had greater bilateral emphysema (No Z=7.8%, MZ=12%, ZS/ZV R =13%, ZZ=24%, p=2.0x10 -7 ), and airtrapping (No Z=25%, MZ=33%, ZS/V R =49%, ZZ=54%, p=2.7x10 -8 ) compared to NHW without PI Z (No Z, N=1,499). Lower lung zone emphysema (p=0.008-0.04) and airtrapping (p=0.005-0.02) was lower in No Z compared to MZ. Upper and lower zone disease was lower in No Z versus ZZ (emphysema upper zones p=0.001-0.002, lower zones pp=1.2x10 -9 -1.2x10 -8 ; airtrapping upper zones p=2.5x10 -5 -0.0004, lower zones p=4.0x10 -9 -9.9x10 -9 ). ZS/ZV R had more upper zone airtrapping versus ZZ (p=0.03-0.04). Conclusions: In NHW, PI Z-containing SERPINA1 genotypes have cumulative effects on emphysema and airtrapping in both the upper and lower lung zones.
- Fitzpatrick, A., Ramratnam, S. K., Mauger, D. T., Gaston, B. M., Bleecker, E. R., Wenzel, S. E., Teague, W. G., Ramratnam, S., Phipatanakul, W., Myers, R., Moore, W. C., Meyers, D. A., Mauger, D., Ly, N., Li, X., Li, H., Levy, B. D., Jarjour, N. N., Israel, E., , Gaston, B., et al. (2016). Reproducibility and stability of severe asthma research program (SARP) clinical cluster phenotypes in SARP3. European Respiratory Journal, 48. doi:10.1183/13993003.congress-2016.oa3033More infoBackground: The SARP1/2 cluster analysis identified 5 clinical asthma phenotypes that reflect inflammatory mechanisms: a spectrum of early onset allergic asthma (Clusters 1,2,4), late onset severe asthma (Cluster 3) and severe asthma with COPD characteristics (Cluster 5). Aims: Evaluate reproducibility and stability of SARP1/2 clinical cluster phenotypes in SARP3, a 3-year longitudinal cohort enriched for severe asthma. Methods: SARP3 subjects > 12 years old (n= 594) were assigned to SARP1/2 clusters using 11 variables and compared to the SARP1/2 cohort (n=1176). Subjects in both SARP1/2 and SARP3 (n=68) were assigned to clusters twice using unique SARP1/2 and 3 data. Results: The SARP3 cohort is skewed toward severe asthma clusters 3(16%), 4(15%) and 5(19%). SARP3 subjects are older with longer disease duration (p Conclusions: All five SARP1/2 clinical cluster phenotypes are reproducible in SARP3 with a shift toward more severe clusters (3,4,5). In a subset of SARP subjects with longitudinal data there was heterogeneity in the progression of disease severity that was associated with changes in baseline lung function. These results suggest that a clinical approach guided by monitoring of lung function could identify patients at risk for disease progression.
- Li, X., Hawkins, G. A., Moore, W. C., Hastie, A. T., Ampleford, E. J., Milosevic, J., Li, H., Busse, W. W., Erzurum, S. C., Kaminski, N., Wenzel, S. E., Bleecker, E. R., & Meyers, D. A. (2016). Expression of asthma susceptibility genes in bronchial epithelial cells and bronchial alveolar lavage in the Severe Asthma Research Program (SARP) cohort. The Journal of asthma : official journal of the Association for the Care of Asthma, 53(8), 775-82.More infoGenome-wide association studies (GWASs) have identified genes associated with asthma, however expression of these genes in asthma-relevant tissues has not been studied. This study tested expression and correlation between GWAS-identified asthma genes and asthma or asthma severity.
- Nieuwenhuis, M. A., Siedlinski, M., van den Berge, M., Granell, R., Li, X., Niens, M., van der Vlies, P., Altmüller, J., Nürnberg, P., Kerkhof, M., van Schayck, O. C., Riemersma, R. A., van der Molen, T., de Monchy, J. G., Bossé, Y., Sandford, A., Bruijnzeel-Koomen, C. A., Gerth van Wijk, R., Ten Hacken, N. H., , Timens, W., et al. (2016). Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma. Allergy, 71(12), 1712-1720.More infoGenomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR.
- Li, X., Hastie, A. T., Hawkins, G. A., Moore, W. C., Ampleford, E. J., Milosevic, J., Li, H., Busse, W. W., Erzurum, S. C., Kaminski, N., Wenzel, S. E., Meyers, D. A., & Bleecker, E. R. (2015). eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes. Allergy, 70(10), 1309-18.More infoGenome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs.
- Bunyavanich, S., Schadt, E. E., Himes, B. E., Lasky-Su, J., Qiu, W., Lazarus, R., Ziniti, J. P., Cohain, A., Linderman, M., Torgerson, D. G., Eng, C. S., Pino-Yanes, M., Padhukasahasram, B., Yang, J. J., Mathias, R. A., Beaty, T. H., Li, X., Graves, P., Romieu, I., , Navarro, B. d., et al. (2014). Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis. BMC medical genomics, 7, 48.More infoAllergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
- Moore, W. C., Hastie, A. T., Li, X., Li, H., Busse, W. W., Jarjour, N. N., Wenzel, S. E., Peters, S. P., Meyers, D. A., Bleecker, E. R., & , N. H. (2014). Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. The Journal of allergy and clinical immunology, 133(6), 1557-63.e5.More infoClinical cluster analysis from the Severe Asthma Research Program (SARP) identified 5 asthma subphenotypes that represent the severity spectrum of early-onset allergic asthma, late-onset severe asthma, and severe asthma with chronic obstructive pulmonary disease characteristics. Analysis of induced sputum from a subset of SARP subjects showed 4 sputum inflammatory cellular patterns. Subjects with concurrent increases in eosinophil (≥2%) and neutrophil (≥40%) percentages had characteristics of very severe asthma.
- Li, X., Hawkins, G. A., Ampleford, E. J., Moore, W. C., Li, H., Hastie, A. T., Howard, T. D., Boushey, H. A., Busse, W. W., Calhoun, W. J., Castro, M., Erzurum, S. C., Israel, E., Lemanske, R. F., Szefler, S. J., Wasserman, S. I., Wenzel, S. E., Peters, S. P., Meyers, D. A., & Bleecker, E. R. (2013). Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. The Journal of allergy and clinical immunology, 132(2), 313-20.e15.More infoRecent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
- Moore, W. C., Fitzpatrick, A. M., Li, X., Hastie, A. T., Li, H., Meyers, D. A., & Bleecker, E. R. (2013). Clinical heterogeneity in the severe asthma research program. Annals of the American Thoracic Society, 10 Suppl, S118-24.More infoThe National Heart, Lung, and Blood Institute has sponsored several asthma clinical networks, but the Severe Asthma Research Program (SARP) is unique, because it is not a clinical trials network, and it includes both adults and children. Investigators in SARP have comprehensively characterized 1,644 patients with asthma over the past 10 years, including 583 individuals with severe asthma and 300 children below the age of 18 years. The diversity in clinical characteristics, physiologic measures, and biomarkers in a large number of subjects across the ages provides an ideal cohort in which to investigate asthma heterogeneity. Using both biased and unbiased approaches, multiple asthma phenotypes have been described in SARP. These phenotypic analyses have improved our understanding of heterogeneity in asthma, and may provide a starting point to transform clinical practice through the evidence-based classification of disease severity. Although these new phenotypes strive to make order out of a heterogeneous group of patients, they are limited by that heterogeneity. There may be large groups of patients, especially those with milder asthma, that can be grouped into a clinical phenotype to guide therapy, but there will always be patients on the "edge" of a phenotype who will not fit into these groupings. In the SARP cluster analysis, subjects on the "edge" of a phenotype frequently had lung function that was better or worse than other subjects in the same cluster, despite similar clinical characteristics. This suggests that different pathophysiologic mechanisms may be responsible for decrements in lung function in some subjects. This is extremely important for subjects with severe asthma who may be on the "edge" of two phenotypes that may be driven by different pathobiologic mechanisms that warrant different therapeutic approaches.
- Hawkins, G. A., Robinson, M. B., Hastie, A. T., Li, X., Li, H., Moore, W. C., Howard, T. D., Busse, W. W., Erzurum, S. C., Wenzel, S. E., Peters, S. P., Meyers, D. A., Bleecker, E. R., & , N. H. (2012). The IL6R variation Asp(358)Ala is a potential modifier of lung function in subjects with asthma. The Journal of allergy and clinical immunology, 130(2), 510-5.e1.More infoThe IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r(2) = 1) with the IL6R coding SNP rs2228145 (Asp(358)Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling.
- Li, X., Ampleford, E. J., Howard, T. D., Moore, W. C., Li, H., Busse, W. W., Castro, M., Erzurum, S. C., Fitzpatrick, A. M., Gaston, B., Israel, E., Jarjour, N. N., Teague, W. G., Wenzel, S. E., Hawkins, G. A., Bleecker, E. R., & Meyers, D. A. (2012). The C11orf30-LRRC32 region is associated with total serum IgE levels in asthmatic patients. The Journal of allergy and clinical immunology, 129(2), 575-8, 578.e1-9.
- Li, X., Ampleford, E. J., Howard, T. D., Moore, W. C., Torgerson, D. G., Li, H., Busse, W. W., Castro, M., Erzurum, S. C., Israel, E., Nicolae, D. L., Ober, C., Wenzel, S. E., Hawkins, G. A., Bleecker, E. R., & Meyers, D. A. (2012). Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. The Journal of allergy and clinical immunology, 130(4), 861-8.e7.More infoGenome-wide association studies (GWASs) of asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB), IL33, IL-1 receptor-like 1 and IL-18 receptor 1 (IL1RL1-IL18R1), RAD50-IL13, thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36), and HLA-DR/DQ regions.
- Slager, R. E., Hawkins, G. A., Li, X., Postma, D. S., Meyers, D. A., & Bleecker, E. R. (2012). Genetics of asthma susceptibility and severity. Clinics in chest medicine, 33(3), 431-43.More infoThis article summarizes major findings in genome-wide studies of asthma susceptibility and severity. Two large meta-analyses identified four chromosomal regions which were consistently associated with development of asthma. Genes that are associated with asthma subphenotypes such as lung function, biomarker levels, and asthma therapeutic responses can provide insight into mechanisms of asthma severity and disease progression. Future genetic studies will incorporate sequencing in comprehensively phenotyped asthmatics to lead to the development of personalized therapy.
- Torgerson, D. G., Capurso, D., Ampleford, E. J., Li, X., Moore, W. C., Gignoux, C. R., Hu, D., Eng, C., Mathias, R. A., Busse, W. W., Castro, M., Erzurum, S. C., Fitzpatrick, A. M., Gaston, B., Israel, E., Jarjour, N. N., Teague, W. G., Wenzel, S. E., Rodríguez-Santana, J. R., , Rodríguez-Cintrón, W., et al. (2012). Genome-wide ancestry association testing identifies a common European variant on 6q14.1 as a risk factor for asthma in African American subjects. The Journal of allergy and clinical immunology, 130(3), 622-629.e9.More infoGenetic variants that contribute to asthma susceptibility might be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations.
- Fitzpatrick, A. M., Teague, W. G., Meyers, D. A., Peters, S. P., Li, X., Li, H., Wenzel, S. E., Aujla, S., Castro, M., Bacharier, L. B., Gaston, B. M., Bleecker, E. R., Moore, W. C., & , N. I. (2011). Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. The Journal of allergy and clinical immunology, 127(2), 382-389.e1-13.More infoAsthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to school-age children with persistent asthma across a wide range of severities.
- Li, X., Howard, T. D., Moore, W. C., Ampleford, E. J., Li, H., Busse, W. W., Calhoun, W. J., Castro, M., Chung, K. F., Erzurum, S. C., Fitzpatrick, A. M., Gaston, B., Israel, E., Jarjour, N. N., Teague, W. G., Wenzel, S. E., Peters, S. P., Hawkins, G. A., Bleecker, E. R., & Meyers, D. A. (2011). Importance of hedgehog interacting protein and other lung function genes in asthma. The Journal of allergy and clinical immunology, 127(6), 1457-65.More infoTwo recent large meta-analyses of genome-wide association studies of lung function in general populations of European descent identified 11 candidate genes/regions. The importance of these genes in lung function in white and African American subjects with asthma is unknown.
- Torgerson, D. G., Ampleford, E. J., Chiu, G. Y., Gauderman, W. J., Gignoux, C. R., Graves, P. E., Himes, B. E., Levin, A. M., Mathias, R. A., Hancock, D. B., Baurley, J. W., Eng, C., Stern, D. A., Celedón, J. C., Rafaels, N., Capurso, D., Conti, D. V., Roth, L. A., Soto-Quiros, M., , Togias, A., et al. (2011). Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nature genetics, 43(9), 887-92.More infoAsthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
- Li, X., Howard, T. D., Zheng, S. L., Haselkorn, T., Peters, S. P., Meyers, D. A., & Bleecker, E. R. (2010). Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. The Journal of allergy and clinical immunology, 125(2), 328-335.e11.More infoAsthma is a heterogeneous disease that is caused by the interaction of genetic susceptibility with environmental influences. Genome-wide association studies (GWASs) represent a powerful approach to investigate the association of DNA variants with disease susceptibility. To date, few GWASs for asthma have been reported.
- Moore, W. C., Meyers, D. A., Wenzel, S. E., Teague, W. G., Li, H., Li, X., D'Agostino, R., Castro, M., Curran-Everett, D., Fitzpatrick, A. M., Gaston, B., Jarjour, N. N., Sorkness, R., Calhoun, W. J., Chung, K. F., Comhair, S. A., Dweik, R. A., Israel, E., Peters, S. P., , Busse, W. W., et al. (2010). Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. American journal of respiratory and critical care medicine, 181(4), 315-23.More infoThe Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma.
- Li, X., Fleis, R. I., Shubitowski, D. M., Ramadas, R. A., & Ewart, S. L. (2007). Fine mapping of murine asthma quantitative trait loci and analyses of Ptgs1 and Mrc1 as positional candidate genes. DNA sequence : the journal of DNA sequencing and mapping, 18(3), 190-5.More infoAsthma is a common respiratory disease that is driven by both genetic and environmental factors. Identification of the genes underlying asthma will provide insight into the mechanisms and treatment of this important disease. Previous studies in this laboratory identified two distinct quantitative trait loci for the asthma-related parameter, allergen-induced airway hyperresponsiveness, in a murine model by means of a genome-wide linkage analysis. The present study focuses and refines the map location of these two loci. Additionally, we explore prostaglandin-endoperoxide synthase-1 (Ptgs1) and mannose receptor C-type 1 (Mrc1) genes as two new positional candidate genes for allergen-induced airway hyperresponsiveness through comparative sequence analysis and mRNA expression studies of mouse strains with genetically mediated airway responsiveness.
- Sun, J., Liu, W., Adams, T. S., Sun, J., Li, X., Turner, A. R., Chang, B., Kim, J. W., Zheng, S. L., Isaacs, W. B., & Xu, J. (2007). DNA copy number alterations in prostate cancers: a combined analysis of published CGH studies. The Prostate, 67(7), 692-700.More infoIdentifying genomic regions that are commonly deleted or gained in neoplastic cells is an important approach to identify tumor suppressor genes and oncogenes. Studies in the last two decades have identified a number of common DNA copy number alterations in prostate cancer. However, because of various sample sizes, diverse tumor types and sources, as well as a variety of detection methods with various sensitivities and resolutions, it is difficult to summarize and fully interpret the overall results.
- Li, X., Wills-Karp, M., & Ewart, S. (2006). Investigating Gata3 as a positional candidate gene for allergic asthma in a murine model. International journal of immunogenetics, 33(5), 333-7.More infoGata3 is a positional candidate gene for allergic asthma. We determined allergen-induced GATA-3 mRNA and protein expression in asthma susceptible and resistant mice and generated Gata3 sequence data. Our data indicate that the Gata3 gene in isolation is not a causative agent of asthma susceptibility in our model.
- Ramadas, R. A., Li, X., Shubitowski, D. M., Samineni, S., Wills-Karp, M., & Ewart, S. L. (2006). IL-1 Receptor antagonist as a positional candidate gene in a murine model of allergic asthma. Immunogenetics, 58(10), 851-5.More infoInterleukin-1 receptor antagonist (IL-1ra) is an inhibitor of the proinflammatory IL-1. The IL-1ra gene (Il1rn) maps near the allergen-induced bronchial hyper-responsiveness-1 locus, Abhr1, which we previously mapped to murine chromosome 2 using A/J (asthma susceptible) and C3H/HeJ (asthma resistant) mice. We evaluated the role of Il1rn in our mouse model by comparing its genomic sequence between A/J and C3H/HeJ mice as well as assessing strain-specific RNA and protein production in response to allergen. We identified no functional sequence variations in the Il1rn gene between A/J and C3H/HeJ mice. Il1rn mRNA and protein were induced by ovalbumin (OVA) exposure in both strains, but to a greater extent in A/J mice at the earlier time points. We examined other IL-1 family members (Il1a, Il1b, Il1f9, and Il1r2) and found OVA-induced expression increases at 6 h, yet only Il1b and Il1f9 had strain-specific differences. Of these, only Il1f9 is located within Abhr1, and we found several non-coding polymorphisms in the Il1f9 gene between A/J and C3H/HeJ mice. Our results exclude Il1rn as the gene for Abhr1 and indicate that Il1f9 warrants further investigation based on genetic and expression differences observed in our mouse model of allergic asthma.
Proceedings Publications
- Bowler, R. P., Bleecker, E. R., Woodruff, P. G., Spiromics, N., Peters, S. P., Paine, R., Ortega, V. E., O'neal, W. K., Moore, W. C., Meyers, D. A., Martinez, F. J., Li, X., Kanner, R. E., Hoffman, E. A., Hawkins, G. A., Hansel, N. N., Han, M. K., Couper, D. J., Cooper, C. B., , Bowler, R. P., et al. (2020). Genome-Wide Association Study of Short-Acting Bronchodilator Response Identifies Novel Pharmacogenetic Loci in SPIROMICS. In D107. ENVIRONMENTAL EXPOSURES AND COPD.
- Mauger, D. T., Levy, B. D., Israel, E., Bowler, R. P., Bleecker, E. R., Zein, J. G., Woodruff, P. G., Wenzel, S. E., Spiromics, N., Sarp, N., Peters, S. P., Paine, R., Ortega, V. E., O'neal, W. K., Moore, W. C., Meyers, D. A., Mauger, D., Martinez, F. J., Liggett, S. B., , Li, X., et al. (2020). Deep Resequencing of the Beta-2 Adrenergic Receptor Gene (ADRB2) in COPD and Asthma Cohorts Identifies Functional Rare Variants. In B94. ADULT AND PEDIATRIC ASTHMA GENETIC STUDIES.
- Bleecker, E. R., Wenzel, S. E., Pr, T. T., Peters, M. C., Moore, W. C., Meyers, D. A., Li, X., Li, H., Levy, B. D., Jarjour, N. N., Israel, E., Hawkins, G. A., Hastie, A. T., Gaston, B. M., Fahy, J. V., Castro, M., & Bleecker, E. R. (2019). Investigation of IL-6 and IL-6R levels as Biomarkers for Asthma Severity and Asthma Exacerbations. In B21. SEVERE ASTHMA: CLINICAL AND MECHANISTIC STUDIES.
- Bleecker, E. R., Woodruff, P. G., Spiromics, N., Peters, S. P., Paine, R., Ortega, V. E., O'neal, W. K., Meyers, D. A., Martinez, F. J., Manichaikul, A., Li, X., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Hawkins, G. A., Hansel, N. N., Han, M. K., Couper, D. J., Cooper, C. B., , Bleecker, E. R., et al. (2019). Genome-Wide Association Study of Acute Exacerbations of COPD Identifies Novel Loci in SPIROMICS. In C43. COPD AND POPULATION HEALTH.
- Bleecker, E. R., Woodruff, P. G., Spiromics, N., Peters, S. P., Paine, R., Ortega, V. E., O'neal, W. K., Newell, J. D., Meyers, D. A., Martinez, F. J., Marion, C. R., Li, X., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Hawkins, G. A., Hansel, N. N., Han, M. K., Genese, F., , Couper, D. J., et al. (2019). Pathogenic Primary Ciliary Dyskinesia Pathway Variants Associate with Disease Severity in At-Risk Smokers and COPD Subjects from SPIROMICS. In C43. COPD AND POPULATION HEALTH.
- Bleecker, E. R., Woodruff, P. G., Spiromics, N., Peters, S. P., Paine, R., Ortega, V. E., O'neal, W. K., Newell, J. D., Meyers, D. A., Martinez, F. J., Marion, C. R., Li, X., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Hawkins, G. A., Hansel, N. N., Han, M. K., Genese, F., , Couper, D. J., et al. (2019). The Rare PI Z Variant Associates with Bronchiectasis in Non-Hispanic White At-Risk Current and Ex-Smokers and COPD Subjects from SPIROMICS. In B64. COPD: MECHANISM AND TREATMENT.
- Bleecker, E. R., Woodruff, P. G., Spiromics, N., Scholand, S., Scholand, M. B., Peters, S. P., Paine, R., Ortega, V. E., O'neal, W. K., Newell, J. D., Meyers, D. A., Martinez, F. J., Li, X., Kleerup, E. C., Kanner, R. E., Hoffman, E. A., Hawkins, G. A., Hansel, N. N., Han, M. K., , Couper, D. J., et al. (2019). Genome-Wide Association Study Identifies Novel Loci and Recapitulates Known Loci for Interstitial Lung Disease in Non-Hispanic Whites from SPIROMICS. In C43. COPD AND POPULATION HEALTH.
- Israel, E., Levy, B. D., Bleecker, E. R., Zein, J. G., Wenzel, S. E., Peters, S. P., Ortega, V. E., Moore, W. C., Meyers, D. A., Li, X., Levy, B. D., Jarjour, N. N., Israel, E., Hawkins, G. A., Fahy, J. V., Erzurum, S. C., Daya, M., Castro, M., Bleecker, E. R., , Barnes, K. C., et al. (2019). Fine-Mapping of Bronchodilator Response Admixture Mapping Peak to Identify Causal Drug Response Genetic Variants. In B32. ASTHMA: MECHANISMS OF DISEASE I.
- Bleecker, E. R., Slager, R. E., Peters, S. P., Moore, W. C., Meyers, D. A., Li, X., Hawkins, G. A., & Bleecker, E. R. (2012). Exome Sequencing Of Asthma Candidate Genes In Chromosome 2q11-12 And 2q33. In C67. TRANSLATIONAL 'OMICS' DISCOVERIES IN LUNG DISEASE.
- Bleecker, E. R., Wenzel, S. E., Moore, W. C., Meyers, D. A., Li, X., Li, H., Howard, T. D., Hawkins, G. A., Erzurum, S. C., Busse, W. W., Bleecker, E. R., & Ampleford, E. J. (2012). Phenotype Determinants For Asthma Severity Clusters And Genetic Association For Cluster-Based Asthma Severity In Severe Asthma Research Program (SARP). In B21. GENETICS OF ASTHMA.
- Bleecker, E. R., Wenzel, S. E., Peters, S. P., Moore, W. C., Meyers, D. A., Li, X., Li, H., Hastie, A. T., Busse, W. W., & Bleecker, E. R. (2012). The Addition Of Sputum Inflammatory Cell Counts To The SARP Cluster Analysis Results In Similar Clinical Asthma Phenotypes With Biologic Heterogeneity. In B92. ASTHMA PHENOTYPES: BETTER UNDERSTANDING OF ASTHMA AND RATIONALE FOR THERAPY.
- Bleecker, E. R., Wenzel, S. E., Teague, W. G., Peters, S. P., Moore, W. C., Meyers, D. A., Li, X., Li, H., Jarjour, N. N., Israel, E., Howard, T. D., Hawkins, G. A., Gaston, B., Fitzpatrick, A. M., Erzurum, S. C., Chung, K. F., Castro, M., Calhoun, W. J., Busse, W. W., , Bleecker, E. R., et al. (2011). Meta-Analyses Of Genome-Wide Association Studies In Five Asthma Populations Identify Novel Genes Associated With Lung Function. In D101. ASTHMA GENETICS.
- Bleecker, E. R., Peters, S. P., Meyers, D. A., Li, X., Howard, T. D., Bleecker, E. R., & Ampleford, E. J. (2010). Genome-wide Association Study Of Asthma Severity Using Proportional Odds Model Identifies TMEM154. In B93. GENOME-WIDE APPROACHES FOR THE IDENTIFICATION OF ASTHMA GENES: NEW METHODS, NEW PHENOTYPES, NEW GENES.