Yann C Klimentidis

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• Bea, J. W., Bea, J. W., Smoller, S., Smoller, S., Wertheim, B. C., Wertheim, B. C., Klimentidis, Y. C., Klimentidis, Y. C., Chen, Z., Chen, Z., Zaslavsky, O., Zaslavsky, O., Manini, T., Manini, T., Womack, C., Womack, C., Kroenke, C., Kroenke, C., LaCroix, A., , LaCroix, A., et al. (2016). Associations between ACE-inhibitors and angiotensin receptor blockers, and lean body mass in community dwelling older women. Nutr, Metab and Cardio Vasc Diseases.
• Cardel, M. I., Lemas, D. J., Lee, A. M., Miller, D. R., Huo, T., Klimentidis, Y. C., & Fernandez, J. R. (2019). Taq1a polymorphism (rs1800497) is associated with obesity-related outcomes and dietary intake in a multi-ethnic sample of children. Pediatric obesity, 14(2), e12470.
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  In adults, the Taq1a polymorphism (rs1800497) near the D2 receptor (DRD2) gene is associated with body mass index and binge eating and is more prevalent among non-Hispanic Blacks (NHB) and Hispanic-Americans (HA) relative to non-Hispanic Whites (NHW). We hypothesize Taq1a polymorphism (rs1800497) risk alleles contribute to paediatric racial/ethnic differences in obesity phenotypes.
• Cardel, M., Lemas, D., Lee, A., Miller, D., Huo, T., Klimentidis, Y. C., & Fernandez, J. (2018). Taq1a polymorphism (rs1800497) is associated with obesity-related outcomes and dietary intake in a multi-ethnic sample of children.. Pediatric Obesity, 14(2).
• Chen, Z., Chen, Z., Klimentidis, Y. C., Klimentidis, Y. C., Bea, J. W., Bea, J. W., Ernst, K. C., Ernst, K. C., Hu, C., Hu, C., Chou, Y., Chou, Y., Jackson, R., Jackson, R., Thomson, C. A., & Thomson, C. A. (2016). Body mass index, waist circumference and mortality in a large mutiethnic postmenopausal cohort - Results from the Women's Health Initiative.. Journal of the American Geriatric Society.
• Chen, Z., Klimentidis, Y. C., Bea, J. W., Ernst, K. C., Hu, C., Chou, Y., Jackson, R., & Thomson, C. A. (2016). Body mass index, waist circumference and mortality in a large mutiethnic postmenopausal cohort - Results from the Women's Health Initiative.. Journal of the American Geriatric Society.
• Choi, K. W., Chen, C. Y., Stein, M. B., Klimentidis, Y. C., Wang, M. J., Koenen, K. C., Smoller, J. W., & , M. D. (2019). Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study. JAMA psychiatry.
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  Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.
• Follis, S. L., Bea, J., Klimentidis, Y., Hu, C., Crandall, C. J., Garcia, D. O., Shadyab, A. H., Nassir, R., & Chen, Z. (2019). Psychosocial stress and bone loss among postmenopausal women: results from the Women's Health Initiative. Journal of epidemiology and community health, 73(9), 888-892.
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  Bone loss is a major public health concern with large proportions of older women experiencing osteoporotic fractures. Previous research has established a relationship between psychosocial stressors and fractures. However, few studies have investigated bone loss as an intermediary in this relationship. This study investigates whether social stress is associated with bone loss during a 6-year period in postmenopausal women.
• German, C. A., Sinsheimer, J. S., Klimentidis, Y. C., Zhou, H., & Zhou, J. J. (2019). Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale. Genetic epidemiology.
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  Logistic regression is the primary analysis tool for binary traits in genome-wide association studies (GWAS). Multinomial regression extends logistic regression to multiple categories. However, many phenotypes more naturally take ordered, discrete values. Examples include (a) subtypes defined from multiple sources of clinical information and (b) derived phenotypes generated by specific phenotyping algorithms for electronic health records (EHR). GWAS of ordinal traits have been problematic. Dichotomizing can lead to a range of arbitrary cutoff values, generating inconsistent, hard to interpret results. Using multinomial regression ignores trait value hierarchy and potentially loses power. Treating ordinal data as quantitative can lead to misleading inference. To address these issues, we analyze ordinal traits with an ordered, multinomial model. This approach increases power and leads to more interpretable results. We derive efficient algorithms for computing test statistics, making ordinal trait GWAS computationally practical for Biobank scale data. Our method is available as a Julia package OrdinalGWAS.jl. Application to a COPDGene study confirms previously found signals based on binary case-control status, but with more significance. Additionally, we demonstrate the capability of our package to run on UK Biobank data by analyzing hypertension as an ordinal trait.
• Klimentidis, Y. C., & Arora, A. (2015). Interaction of Insulin Resistance and Related Genetic Variants with Triglyceride-Associated Genetic Variants. Circulation: Cardiovascular Genetics.
• Klimentidis, Y. C., Bea, J. W., Chen, Z., Klimecki, W., & Hu, C. (2015). Genetic Variant in ACVR2B Is Associated with Lean Mass. Medicine & Science in Sports & Exercise.
• Klimentidis, Y. C., Bea, J. W., Thompson, P., Klimecki, W. T., Hu, C., Wu, G., Nicholas, S., Ryckman, K. K., & Chen, Z. (2014). Genetic variant in ACVR2B is associated with lean mass. WHI P&P / Journal TBD.
• Klimentidis, Y. C., Chougule, A., Arora, A., Frazier-Wood, A. C., & Hsu, C. (2014). Triglyceride-increasing alleles associated with protection against type-2 diabetes. PLoS Genetics.
• Klimentidis, Y. C., Going, S. B., Chen, Z., Lohman, T. G., & Bea, J. W. (2014). High genetic-risk individuals benefit less from resistance exercise intervention. International Journal of Obesity.
• Klimentidis, Y. C., Hibler, E. A., Jurutka, P. W., Kohler, L., Lance, P., Roe, D., Thompson, P. A., & Jacobs, E. T. (2014). CYP24A1 and CYP27B1 polymorphisms, concentrations of vitamin D metabolites, and odds of colorectal adenoma recurrence. Genes and Nutrition.
• Klimentidis, Y. C., Zhou, J., & Kittles, R. A. (2015). Among men only, West-African genetic ancestry is associated with lower central adiposity. International Journal of Obesity.
• Lebron-Aldea, D., Dhurandhar, E. J., Perez-Rodriguez, P., Klimentidis, Y. C., Tiwari, H. K., & Vazquez, A. I. (2014). Genome-enabled models for type 2 diabetes risk assessment. Frontiers in Genetics.
• Lemas, D. J., Klimentidis, Y. C., Tiwari, H., Boyer, B., Wiener, H., & Fernandez, J. (2014). Polymorphisms in SCD and SREBF1 Interact with n-3 Polyunsaturated Fatty Acid Intake to Modify Genetic Associations with Obesity-Related Anthropometric and Metabolic Phenotypes in Yup’ik People. Journal of Lipid Research.
• Morrill, K. E., Lopez-Pentecost, M., Ballesteros, G., Pfander, J. L., Hingle, M. D., Klimentidis, Y. C., Thomson, C. A., & Garcia, D. O. (2019). Weight loss interventions for Hispanic women in the USA: a protocol for a systematic review. Systematic reviews, 8(1), 301.
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  In the U.S., Hispanic women experience a disproportionate rate of obesity and obesity-related chronic diseases. At the same time, Hispanic women remain considerably underrepresented in behavioral weight loss interventions. The purpose of this review is to systematically evaluate the evidence related to the effectiveness of weight loss interventions among Hispanic women in the U.S. This review will identify elements of successful weight loss interventions as well as areas for future research.
• Raichlen, D. A., Klimentidis, Y. C., Bharadwaj, P. K., & Alexander, G. E. (2019). Differential associations of engagement in physical activity and estimated cardiorespiratory fitness with brain volume in middle-aged to older adults. Brain imaging and behavior.
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  Previous work has confirmed the benefits of aerobic exercise for brain aging, however mechanisms underlying these effects remain unclear. Two measures of exercise, time spent in moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF), may reflect different pathways linking activity to brain health. Using data from the UK Biobank, the largest sample combining neuroimaging and objectively measured MVPA available to date (n = 7148, n = 3062, n = 4086; age = 62.14 ± 7.40 years), we found that, when adjusted for covariates including MVPA, CRF was positively associated with overall gray matter volume (FDR p = 1.28E-05). In contrast, when adjusted for covariates including CRF, MVPA was positively associated with left and right hippocampal (FDR p = 0.01; FDR p = 0.02) volumes, but not overall gray matter volume. Both CRF and MVPA were inversely associated with white matter hyperintensity lesion loads (FDR p = 0.002; p = 0.02). Our results suggest separable effects of engagement in exercise behaviors (MVPA) and the physiological effects of exercise (CRF) on structural brain volumes, which may have implications for differential pathways linking exercise and brain benefits.
• Raichlen, D. A., Klimentidis, Y. C., Hsu, C., & Alexander, G. E. (2017). Fractal complexity of daily physical activity patterns differs with age over the lifespan and predicts mortality in older adults. multiple journals (Science, then JAMA, now at PNAS).
• Santos, E. M., Coalson, J. E., Jacobs, E. T., Klimentidis, Y. C., Munga, S., Agawo, M., Anderson, E., Stroupe, N., & Ernst, K. C. (2019). Bed net care practices and associated factors in western Kenya. Malaria journal, 18(1), 274.
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  Insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs) are effective for malaria prevention and are designed to provide nearly 5 years of mosquito protection. However, many ITNs and LLINs become damaged and ineffective for mosquito bite prevention within 1 to 2 years in field conditions. Non-adherence to recommended bed net care and repair practices may partially explain this shortened net longevity.
• Thomson, C. A., LaCroix, A., Kroenke, C., Womack, C., Manini, T., Zaslavsky, O., Chen, Z., Klimentidis, Y. C., Wertheim, B. C., Smoller, S., & Bea, J. W. (2017). Associations between ACE-inhibitors and angiotensin receptor blockers, and lean body mass in community dwelling older women. Journal of Aging Research.
• Vazquez, A. I., Klimentidis, Y. C., Dhurandhar, E. J., Veturi, Y. C., & Perez-Rodriguez, P. (2014). Assessment of Whole-Genome Regression for Type II Diabetes. PLoS One.
• Bea, J. W., Wassertheil-Smoller, S., Wertheim, B. C., Klimentidis, Y., Chen, Z., Zaslavsky, O., Manini, T. M., Womack, C. R., Kroenke, C. H., LaCroix, A. Z., & Thomson, C. A. (2018). Associations between ACE-Inhibitors, Angiotensin Receptor Blockers, and Lean Body Mass in Community Dwelling Older Women. Journal of aging research, 2018, 8491092.
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  Studies suggest that ACE-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) may preserve skeletal muscle with aging. We evaluated longitudinal differences in lean body mass (LBM) among women diagnosed with hypertension and classified as ACE-I/ARB users and nonusers among Women's Health Initiative participants that received dual energy X-ray absorptiometry scans to estimate body composition (=10,635) at baseline and at years 3 and 6 of follow-up. Of those, 2642 were treated for hypertension at baseline. Multivariate linear regression models, adjusted for relevant demographics, behaviors, and medications, assessed ACE-I/ARB use/nonuse and LBM associations at baseline, as well as change in LBM over 3 and 6 years. Although BMI did not differ by ACE-I/ARB use, LBM (%) was significantly higher in ACE-I/ARB users versus nonusers at baseline (52.2% versus 51.3%, resp., =0.001). There was no association between ACE-I/ARB usage and change in LBM over time. Reasons for higher LBM with ACE-I/ARB use cross sectionally, but not longitundinally, are unclear and may reflect a threshold effect of these medications on LBM that is attenuated over time. Nevertheless, ACE-I/ARB use does not appear to negatively impact LBM in the long term.
• Bhagwandin, C., Ashbeck, E. L., Whalen, M., Bandola-Simon, J., Roche, P. A., Szajman, A., Truong, S. M., Wertheim, B. C., Klimentidis, Y. C., Ishido, S., Renquist, B. J., & Lybarger, L. (2018). The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. PloS one, 13(10), e0204898.
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  Type 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells. MARCH1 was recently found to negatively regulate the cell surface levels of the insulin receptor via ubiquitination. This, in turn, impaired insulin sensitivity in mouse models. Here, we report that MARCH1-deficient (knockout; KO) female mice exhibit excessive weight gain and excessive visceral adiposity when reared on standard chow diet, without increased inflammatory cell infiltration of adipose tissue. By contrast, male MARCH1 KO mice had similar weight gain and visceral adiposity to wildtype (WT) male mice. MARCH1 KO mice of both sexes were more glucose tolerant than WT mice. The levels of insulin receptor were generally higher in insulin-responsive tissues (especially the liver) from female MARCH1 KO mice compared to males, with the potential to account in part for the differences between male and female MARCH1 KO mice. We also explored a potential role for MARCH1 in human type 2 diabetes risk through genetic association testing in publicly-available datasets, and found evidence suggestive of association. Collectively, our data indicate an additional link between immune function and diabetes, specifically implicating MARCH1 as a regulator of lipid metabolism and glucose tolerance, whose function is modified by sex-specific factors.
• Klimentidis, Y. C., Raichlen, D. A., Bea, J., Garcia, D. O., Wineinger, N. E., Mandarino, L. J., Alexander, G. E., Chen, Z., & Going, S. B. (2018). Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants identifies multiple variants including CADM2 and APOE. International journal of obesity (2005), 42(6), 1161-1176.
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  Physical activity (PA) protects against a wide range of diseases. Habitual PA appears to be heritable, motivating the search for specific genetic variants that may inform efforts to promote PA and target the best type of PA for each individual.
• Klimentidis, Y. C., Raichlen, D. A., Bea, J., Garcia, D. O., Wineinger, N. E., Mandarino, L. J., Alexander, G. E., Chen, Z., & Going, S. B. (2018). In response to: 'Information bias in measures of self-reported physical activity'. International journal of obesity (2005), 42(12), 2064-2065.
• Raichlen, D. A., Klimentidis, Y. C., Hsu, C. H., & Alexander, G. E. (2018). Fractal complexity of daily physical activity patterns differs with age over the lifespan and is associated with mortality in older adults. The journals of gerontology. Series A, Biological sciences and medical sciences.
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  Accelerometers are included in a wide range of devices that monitor and track physical activity for health-related applications. However, the clinical utility of the information embedded in their rich time-series data has been greatly understudied and has yet to be fully realized. Here, we examine the potential for fractal complexity of actigraphy data to serve as a clinical biomarker for mortality risk.
• Thomson, C. A., Jackson, R., Chou, Y., Hu, C., Ernst, K. C., Bea, J. W., Klimentidis, Y. C., & Chen, Z. (2017). Body mass index, waist circumference and mortality in a large mutiethnic postmenopausal cohort - Results from the Women's Health Initiative.. Journal of the American Geriatric Society.
• Klimentidis, Y. C., & Arora, A. (2016). Interaction of Insulin Resistance and Related Genetic Variants With Triglyceride-Associated Genetic Variants. Circulation. Cardiovascular genetics, 9(2), 154-61.
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  Several studies suggest that some triglyceride-associated single-nucleotide polymorphisms (SNPs) have pleiotropic and opposite effects on glycemic traits. This potentially implicates them in pathways such as de novo lipogenesis, which is presumably upregulated in the context of insulin resistance. We therefore tested whether the association of triglyceride-associated SNPs with triglyceride levels differs according to one's level of insulin resistance.
• Klimentidis, Y. C., Arora, A., Zhou, J., Kittles, R., & Allison, D. B. (2016). The Genetic Contribution of West-African Ancestry to Protection against Central Obesity in African-American Men but Not Women: Results from the ARIC and MESA Studies. Frontiers in genetics, 7, 89.
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  Over 80% of African-American (AA) women are overweight or obese. A large racial disparity between AA and European-Americans (EA) in obesity rates exists among women, but curiously not among men. Although socio-economic and/or cultural factors may partly account for this race-by-sex interaction, the potential involvement of genetic factors has not yet been investigated. Among 2814 self-identified AA in the Atherosclerosis Risk in Communities study, we estimated each individual's degree of West-African genetic ancestry using 3437 ancestry informative markers. We then tested whether sex modifies the association between West-African genetic ancestry and body mass index (BMI), waist-circumference (WC), and waist-to-hip ratio (WHR), adjusting for income and education levels, and examined associations of ancestry with the phenotypes separately in males and females. We replicated our findings in the Multi-Ethnic Study of Atherosclerosis (n = 1611 AA). In both studies, we find that West-African ancestry is negatively associated with obesity, especially central obesity, among AA men, but not among AA women (pinteraction = 4.14 × 10(-5) in pooled analysis of WHR). In conclusion, our results suggest that the combination of male gender and West-African genetic ancestry is associated with protection against central adiposity, and suggest that the large racial disparity that exists among women, but not men, may be at least partly attributed to genetic factors.
• Klimentidis, Y. C., Bea, J. W., Thompson, P., Klimecki, W. T., Hu, C., Wu, G., Nicholas, J. S., Ryckman, K. K., & Chen, Z. (2016). Genetic Variant in ACVR2B Is Associated with Lean Mass. Medicine and science in sports and exercise, 48(7), 1270-5.
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  Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait.
• Lemas, D. J., Klimentidis, Y. C., Aslibekyan, S., Wiener, H. W., O'Brien, D. M., Hopkins, S. E., Stanhope, K. L., Havel, P. J., Allison, D. B., Fernandez, J. R., Tiwari, H. K., & Boyer, B. B. (2016). Polymorphisms in stearoyl coa desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people. Molecular nutrition & food research, 60(12), 2642-2653.
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  n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity; however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin-sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes.
• Duarte, C. W., Klimentidis, Y. C., Harris, J. J., Cardel, M., & Fernández, J. R. (2015). Discovery of phenotypic networks from genotypic association studies with application to obesity. International journal of data mining and bioinformatics, 12(2), 129-43.
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  Genome-wide Association Studies (GWAS) have resulted in many discovered risk variants for several obesity-related traits. However, before clinical relevance of these discoveries can be achieved, molecular or physiological mechanisms of these risk variants needs to be discovered. One strategy is to perform data mining of phenotypically-rich data sources such as those present in dbGAP (database of Genotypes and Phenotypes) for hypothesis generation. Here we propose a technique that combines the power of existing Bayesian Network (BN) learning algorithms with the statistical rigour of Structural Equation Modelling (SEM) to produce an overall phenotypic network discovery system with optimal properties. We illustrate our method using the analysis of a candidate SNP data set from the AMERICO sample, a multi-ethnic cross-sectional cohort of roughly 300 children with detailed obesity-related phenotypes. We demonstrate our approach by showing genetic mechanisms for three obesity-related SNPs.
• Hibler, E. A., Klimentidis, Y. C., Jurutka, P. W., Kohler, L. N., Lance, P., Roe, D. J., Thompson, P. A., & Jacobs, E. T. (2015). CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence. Nutrition and cancer, 67(7), 1131-41.
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  Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1α,25-hydroxyvitamin D [1,25(OH)2D]. This study examined associations between CYP27B1 and CYP24A1 polymorphisms, circulating 25(OH)D and 1,25(OH)2D concentrations, and colorectal adenoma recurrence in a pooled sample from 2 clinical trials (n = 1,188). Nominal associations were observed between increasing copies of the T allele in CYP24A1 rs927650 and 25(OH)D concentrations (P = 0.02); as well as colorectal adenoma recurrence, with odds ratios (95% confidence intervals) of 1.30 (0.99-1.70) and 1.38 (1.01-1.89) for heterozygotes and minor allele homozygotes, respectively (P = 0.04). In addition, a statistically significant relationship between CYP24A1 rs35051736, a functional polymorphism, and odds for advanced colorectal adenoma recurrence was observed (P < 0.001). Further, nominally statistically significant interactions were observed between rs2296241 and 25(OH)D as well as rs2762939 and 1,25(OH)2D (P(interaction) = 0.10, respectively). Overall, CYP24A1 polymorphisms may influence the development of advanced lesions, and modify the effect of vitamin D metabolites on adenoma recurrence. Further study is necessary to characterize the differences between circulating vitamin D metabolite measurements compared to cellular level activity in relation to cancer risk.
• Klimentidis, Y. C., Arora, A., Chougule, A., Zhou, J., & Raichlen, D. A. (2015). FTO association and interaction with time spent sitting. International journal of obesity (2005).
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  Multiple studies have revealed an interaction between a variant in the FTO gene and self-reported physical activity on body mass index (BMI). Physical inactivity, such as time spent sitting (TSS) has recently gained attention as an important risk factor for obesity and related diseases. It is possible that FTO interacts with TSS to affect BMI, and/or that FTO's putative effect on BMI is mediated through TSS.
• Klimentidis, Y. C., Bea, J. W., Lohman, T. G., Hsieh, P. S., Going, S. B., & Chen, Z. (2015). Resistance exercise intervention results in less weight loss among individuals at high genetic risk for obesity. International Journal of Obesity, 39(9), 1371-1375.
• Klimentidis, Y. C., Bea, J. W., Lohman, T., Hsieh, P., Going, S., & Chen, Z. (2015). High genetic risk individuals benefit less from resistance exercise intervention. International journal of obesity (2005), 39(9), 1371-5.
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  Genetic factors have an important role in body mass index (BMI) variation, and also likely have a role in the weight loss and body composition response to physical activity/exercise. With the recent identification of BMI-associated genetic variants, it is possible to investigate the interaction of these genetic factors with exercise on body composition outcomes.
• Klimentidis, Y. C., Chougule, A., Arora, A., Frazier-Wood, A. C., & Hsu, C. (2015). Triglyceride-Increasing Alleles Associated with Protection against Type-2 Diabetes. PLoS genetics, 11(5), e1005204.
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  Elevated plasma triglyceride (TG) levels are an established risk factor for type-2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body- mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p
• Lebrón-Aldea, D., Dhurandhar, E. J., Pérez-Rodríguez, P., Klimentidis, Y. C., Tiwari, H. K., & Vazquez, A. I. (2015). Integrated genomic and BMI analysis for type 2 diabetes risk assessment. Frontiers in genetics, 6, 75.
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  Type 2 Diabetes (T2D) is a chronic disease arising from the development of insulin absence or resistance within the body, and a complex interplay of environmental and genetic factors. The incidence of T2D has increased throughout the last few decades, together with the occurrence of the obesity epidemic. The consideration of variants identified by Genome Wide Association Studies (GWAS) into risk assessment models for T2D could aid in the identification of at-risk patients who could benefit from preventive medicine. In this study, we build several risk assessment models, evaluated with two different classification approaches (Logistic Regression and Neural Networks), to measure the effect of including genetic information in the prediction of T2D. We used data from to the Original and the Offspring cohorts of the Framingham Heart Study, which provides phenotypic and genetic information for 5245 subjects (4306 controls and 939 cases). Models were built by using several covariates: gender, exposure time, cohort, body mass index (BMI), and 65 SNPs associated to T2D. We fitted Logistic Regressions and Bayesian Regularized Neural Networks and then assessed their predictive ability by using a ten-fold cross validation. We found that the inclusion of genetic information into the risk assessment models increased the predictive ability by 2%, when compared to the baseline model. Furthermore, the models that included BMI at the onset of diabetes as a possible effector, gave an improvement of 6% in the area under the curve derived from the ROC analysis. The highest AUC achieved (0.75) belonged to the model that included BMI, and a genetic score based on the 65 established T2D-associated SNPs. Finally, the inclusion of SNPs and BMI raised predictive ability in all models as expected; however, results from the AUC in Neural Networks and Logistic Regression did not differ significantly in their prediction accuracy.
• Reynolds, R. J., Vazquez, A. I., Srinivasasainagendra, V., Klimentidis, Y. C., Bridges, S. L., Allison, D. B., & Singh, J. A. (2015). Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index. Rheumatology international.
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  We hypothesized that serum urate-associated SNPs, individually or collectively, interact with BMI and renal disease to contribute to risk of incident gout. We measured the incidence of gout and associated comorbidities using the original and offspring cohorts of the Framingham Heart Study. We used direct and imputed genotypes for eight validated serum urate loci. We fit binomial regression models of gout incidence as a function of the covariates, age, type 2 diabetes, sex, and all main and interaction effects of the eight serum urate SNPs with BMI and renal disease. Models were also fit with a genetic risk score for serum urate levels which corresponds to the sum of risk alleles at the eight SNPs. Model covariates, age (P = 5.95E-06), sex (P = 2.46E-39), diabetes (P = 2.34E-07), BMI (P = 1.14E-11) and the SNPs, rs1967017 (P = 9.54E-03), rs13129697 (P = 4.34E-07), rs2199936 (P = 7.28E-03) and rs675209 (P = 4.84E-02) were all associated with incident gout. No BMI by SNP or BMI by serum urate genetic risk score interactions were statistically significant, but renal disease by rs1106766 was statistically significant (P = 6.12E-03). We demonstrated that minor alleles of rs1106766 (intergenic, INHBC) were negatively associated with the risk of incident gout in subjects without renal disease, but not for individuals with renal disease. These analyses demonstrate that a significant component of the risk of gout may involve complex interplay between genes and environment.
• Vazquez, A. I., Klimentidis, Y. C., Dhurandhar, E. J., Veturi, Y. C., & Paérez-Rodríguez, P. (2015). Assessment of whole-genome regression for type II diabetes. PloS one, 10(4), e0123818.
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  Lifestyle and genetic factors play a large role in the development of Type 2 Diabetes (T2D). Despite the important role of genetic factors, genetic information is not incorporated into the clinical assessment of T2D risk. We assessed and compared Whole Genome Regression methods to predict the T2D status of 5,245 subjects from the Framingham Heart Study. For evaluating each method we constructed the following set of regression models: A clinical baseline model (CBM) which included non-genetic covariates only. CBM was extended by adding the first two marker-derived principal components and 65 SNPs identified by a recent GWAS consortium for T2D (M-65SNPs). Subsequently, it was further extended by adding 249,798 genome-wide SNPs from a high-density array. The Bayesian models used to incorporate genome-wide marker information as predictors were: Bayes A, Bayes Cπ, Bayesian LASSO (BL), and the Genomic Best Linear Unbiased Prediction (G-BLUP). Results included estimates of the genetic variance and heritability, genetic scores for T2D, and predictive ability evaluated in a 10-fold cross-validation. The predictive AUC estimates for CBM and M-65SNPs were: 0.668 and 0.684, respectively. We found evidence of contribution of genetic effects in T2D, as reflected in the genomic heritability estimates (0.492±0.066). The highest predictive AUC among the genome-wide marker Bayesian models was 0.681 for the Bayesian LASSO. Overall, the improvement in predictive ability was moderate and did not differ greatly among models that included genetic information. Approximately 58% of the total number of genetic variants was found to contribute to the overall genetic variation, indicating a complex genetic architecture for T2D. Our results suggest that the Bayes Cπ and the G-BLUP models with a large set of genome-wide markers could be used for predicting risk to T2D, as an alternative to using high-density arrays when selected markers from large consortiums for a given complex trait or disease are unavailable.
• Aslibekyan, S., Vaughan, L. K., Wiener, H. W., Lemas, D. J., Klimentidis, Y. C., Havel, P. J., Stanhope, K. L., O'brien, D. M., Hopkins, S. E., Boyer, B. B., & Tiwari, H. K. (2014). Evidence for novel genetic loci associated with metabolic traits in Yup'ik people. American journal of human biology : the official journal of the Human Biology Council, 25(5).
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  To identify genomic regions associated with fasting plasma lipid profiles, insulin, glucose, and glycosylated hemoglobin in a Yup'ik study population, and to evaluate whether the observed associations between genetic factors and metabolic traits were modified by dietary intake of marine derived omega-3 polyunsaturated acids (n-3 PUFA).
• Klimentidis, Y. C., Chen, Z., Arora, A., & Hsu, C. (2014). Association of physical activity with lower type 2 diabetes incidence is weaker among individuals at high genetic risk. Diabetologia, 57(12), 2530-4.
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  We examined whether or not the association of physical activity with type 2 diabetes incidence differs according to several types of genetic susceptibility.
• Klimentidis, Y. C., Wineinger, N. E., Vazquez, A. I., & de Los Campos, G. (2014). Multiple metabolic genetic risk scores and type 2 diabetes risk in three racial/ethnic groups. The Journal of clinical endocrinology and metabolism, 99(9), E1814-8.
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  CONTEXT/RATIONALE: Meta-analyses of genome-wide association studies have identified many single-nucleotide polymorphisms associated with various metabolic and cardiovascular traits, offering us the opportunity to learn about and capitalize on the links between cardiometabolic traits and type 2 diabetes (T2D).
• Klimentidis, Y. C., Zhou, J., & Wineinger, N. E. (2014). Identification of allelic heterogeneity at type-2 diabetes loci and impact on prediction. PloS one, 9(11), e113072.
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  Although over 60 single nucleotide polymorphisms (SNPs) have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D) among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs--a phenomenon often referred to as allelic heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p
• Chen, G., Liu, N., Klimentidis, Y. C., Zhu, X., Zhi, D., Wang, X., & Lou, X. (2013). A unified GMDR method for detecting gene-gene interactions in family and unrelated samples with application to nicotine dependence. Human genetics.
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  Gene-gene and gene-environment interactions govern a substantial portion of the variation in complex traits and diseases. In convention, a set of either unrelated or family samples are used in detection of such interactions; even when both kinds of data are available, the unrelated and the family samples are analyzed separately, potentially leading to loss in statistical power. In this report, to detect gene-gene interactions we propose a generalized multifactor dimensionality reduction method that unifies analyses of nuclear families and unrelated subjects within the same statistical framework. We used principal components as genetic background controls against population stratification, and when sibling data are included, within-family control were used to correct for potential spurious association at the tested loci. Through comprehensive simulations, we demonstrate that the proposed method can remarkably increase power by pooling unrelated and offspring's samples together as compared with individual analysis strategies and the Fisher's combining p value method while it retains a controlled type I error rate in the presence of population structure. In application to a real dataset, we detected one significant tetragenic interaction among CHRNA4, CHRNB2, BDNF, and NTRK2 associated with nicotine dependence in the Study of Addiction: Genetics and Environment sample, suggesting the biological role of these genes in nicotine dependence development.
• Klimentidis, Y. C., Lemas, D. J., Wiener, H. H., O'Brien, D. M., Havel, P. J., Stanhope, K. L., Hopkins, S. E., Tiwari, H. K., & Boyer, B. B. (2013). CDKAL1 and HHEX are associated with type-2 diabetes-related traits among Yup'ik people. Journal of diabetes.
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  Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with type-2 diabetes (T2D), mainly among individuals of European ancestry. We examined the frequency of these SNPs and their association with T2D-related traits in an Alaska Native study population with a historically low prevalence of T2D. We also investigated whether dietary characteristics that may protect against T2D, such as n-3 polyunsaturated fatty acid (n-3 PUFA) intake, modify these associations.
• Klimentidis, Y. C., Vazquez, A. I., de Los Campos, G., Allison, D. B., Dransfield, M. T., & Thannickal, V. J. (2013). Heritability of pulmonary function estimated from pedigree and whole-genome markers. Frontiers in genetics, 4.
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  Asthma and chronic obstructive pulmonary disease (COPD) are major worldwide health problems. Pulmonary function testing is a useful diagnostic tool for these diseases, and is known to be influenced by genetic and environmental factors. Previous studies have demonstrated that a substantial proportion of the variation in pulmonary function phenotypes can be explained by familial relationships. The availability of whole-genome single nucleotide polymorphism (SNP) data enables us to further evaluate the extent to which genetic factors account for variation in pulmonary function and to compare pedigree- to SNP-based estimates of heritability. Here, we employ methods developed in the animal breeding field to estimate the heritability of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of these two measures (FEV1/FVC) among subjects in the Framingham Heart Study dataset. We compare heritability estimates based on pedigree-based relationships to those based on genome-wide SNPs. We find that, in a family-based study, estimates of heritability using SNP data are nearly identical to estimates based on pedigree information, and range from 0.50 for FEV1 to 0.66 for FEV1/FVC. Therefore, we conclude that genetic factors account for a sizable proportion of inter-individual differences in pulmonary function, and that estimates of heritability based on SNP data are nearly identical to estimates based on pedigree data. Finally, our findings suggest a higher heritability for FEV1/FVC compared to either FEV1 or FVC.
• Lemas, D. J., Klimentidis, Y. C., Wiener, H. H., O'Brien, D. M., Hopkins, S. E., Allison, D. B., Fernandez, J. R., Tiwari, H. K., & Boyer, B. B. (2013). Obesity polymorphisms identified in genome-wide association studies interact with n-3 polyunsaturated fatty acid intake and modify the genetic association with adiposity phenotypes in Yup'ik people. Genes & nutrition, 8(5).
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  n-3 Polyunsaturated fatty acids (n-3 PUFAs) have anti-obesity effects that may modulate risk of obesity, in part, through interactions with genetic factors. Genome-wide association studies (GWAS) have identified genetic variants associated with body mass index (BMI); however, the extent to which these variants influence adiposity through interactions with n-3 PUFAs remains unknown. We evaluated 10 highly replicated obesity GWAS single nucleotide polymorphisms (SNPs) for individual and cumulative associations with adiposity phenotypes in a cross-sectional sample of Yup'ik people (n = 1,073) and evaluated whether genetic associations with obesity were modulated by n-3 PUFA intake. A genetic risk score (GRS) was calculated by adding the BMI-increasing alleles across all 10 SNPs. Dietary intake of n-3 PUFAs was estimated using nitrogen stable isotope ratio (δ(15)N) of red blood cells, and genotype-phenotype analyses were tested in linear models accounting for familial correlations. GRS was positively associated with BMI (p = 0.012), PBF (p = 0.022), ThC (p = 0.025), and waist circumference (p = 0.038). The variance in adiposity phenotypes explained by the GRS included BMI (0.7 %), PBF (0.3 %), ThC (0.7 %), and WC (0.5 %). GRS interactions with n-3 PUFAs modified the association with adiposity and accounted for more than twice the phenotypic variation (~1-2 %), relative to GRS associations alone. Obesity GWAS SNPs contribute to adiposity in this study population of Yup'ik people and interactions with n-3 PUFA intake potentiated the risk of fat accumulation among individuals with high obesity GRS. These data suggest the anti-obesity effects of n-3 PUFAs among Yup'ik people may, in part, be dependent upon an individual's genetic predisposition to obesity.
• Malek, A. J., Klimentidis, Y. C., Kell, K. P., & Fernández, J. R. (2013). Associations of the lactase persistence allele and lactose intake with body composition among multiethnic children. Genes & nutrition, 8(5).
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  Childhood obesity is a worldwide health concern with a multifaceted and sometimes confounding etiology. Dairy products have been implicated as both pro- and anti-obesogenic, perhaps due to the confounding relationship between dairy, lactose consumption, and potential genetic predisposition. We aimed to understand how lactase persistence influenced obesity-related traits by observing the relationships among lactose consumption, a single nucleotide polymorphism (SNP) near the lactase (LCT) gene and body composition parameters in a sample of multiethnic children (n = 296, 7-12 years old). We hypothesized that individuals with the lactase persistence (LP) allele of the LCT SNP (rs4988235) would exhibit a greater degree of adiposity and that this relationship would be mediated by lactose consumption. Body composition variables were measured using dual X-ray absorptiometry and a registered dietitian assessed dietary intake of lactose. Statistical models were adjusted for sex, age, pubertal stage, ethnic group, genetic admixture, socio-economic status, and total energy intake. Our findings indicate a positive, significant association between the LP allele and body mass index (p = 0.034), fat mass index (FMI) (p = 0.043), and waist circumference (p = 0.008), with associations being stronger in males than in females. Our results also reveal that lactose consumption is positively and nearly significantly associated with FMI.
• de Los Campos, G., Vazquez, A. I., Fernando, R., Klimentidis, Y. C., & Sorensen, D. (2013). Prediction of complex human traits using the genomic best linear unbiased predictor. PLoS genetics, 9(7).
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  Despite important advances from Genome Wide Association Studies (GWAS), for most complex human traits and diseases, a sizable proportion of genetic variance remains unexplained and prediction accuracy (PA) is usually low. Evidence suggests that PA can be improved using Whole-Genome Regression (WGR) models where phenotypes are regressed on hundreds of thousands of variants simultaneously. The Genomic Best Linear Unbiased Prediction (G-BLUP, a ridge-regression type method) is a commonly used WGR method and has shown good predictive performance when applied to plant and animal breeding populations. However, breeding and human populations differ greatly in a number of factors that can affect the predictive performance of G-BLUP. Using theory, simulations, and real data analysis, we study the performance of G-BLUP when applied to data from related and unrelated human subjects. Under perfect linkage disequilibrium (LD) between markers and QTL, the prediction R-squared (R(2)) of G-BLUP reaches trait-heritability, asymptotically. However, under imperfect LD between markers and QTL, prediction R(2) based on G-BLUP has a much lower upper bound. We show that the minimum decrease in prediction accuracy caused by imperfect LD between markers and QTL is given by (1-b)(2), where b is the regression of marker-derived genomic relationships on those realized at causal loci. For pairs of related individuals, due to within-family disequilibrium, the patterns of realized genomic similarity are similar across the genome; therefore b is close to one inducing small decrease in R(2). However, with distantly related individuals b reaches very low values imposing a very low upper bound on prediction R(2). Our simulations suggest that for the analysis of data from unrelated individuals, the asymptotic upper bound on R(2) may be of the order of 20% of the trait heritability. We show how PA can be enhanced with use of variable selection or differential shrinkage of estimates of marker effects.

Presentations

• Klimentidis, Y. C. (2019, April). Genetic Basis of Lipedema and Physiological Insight. Fat Disorders Research Society Conference. Baltimore, MD.
• Klimentidis, Y. C. (2019, June). Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants. Behavior Genetics Association annual meeting. Stockholm, Sweden.
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  I was invited to orally present my research as part of a session at this conference.
• Klimentidis, Y. C. (2019, October). LDL-C and type-2 diabetes: an inverse phenotypic association and genetic drivers in the UK Biobank.. American Society of Human Genetics annual conference. Houston, TX.
• Klimentidis, Y. C. (2018, April). Genetic factors underlying the lipedema phenotype. Fat Disorders Research Society Annual Meeting. Dallas, TX.
• Klimentidis, Y. C. (2018, December). Genetic risk factors for lipedema. Lipedema Foundation Scientific Retreat. Washington DC: Lipedema Foundation.
• Klimentidis, Y. C. (2018, February). The genetic basis of physical activity behavior. Invited Talk at the 13th Annual Building Healthy Lifestyles Conference. Arizona State University: Arizona State University.
• Klimentidis, Y. C. (2016, November 2016). Cardiometabolic disease and cancer: a genetic perspective. UA Cancer Prevention and Control Seminar Series. UA Cancer Center: UA Cancer Prevention and Control Program.
• Klimentidis, Y. C., Zhou, J., Kittles, R. A., Allison, D. B., & Arora, A. (2016, Summer). West-African genetic ancestry is associated with a more favorable cardiometabolic profile among men: a phenomenon partly explained by a variant near COL3A1 and DIRC1. American Diabetes Association Scientific Sessions. New Orleans, LA: American Diabetes Association.
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  I presented this poster at the annual national meeting of the American Diabetes Association.
• Klimentidis, Y. C. (2015, May). Type-2 Diabetes: When Genes Meet Lifestyle. University of Arizona Genetics and Genomics Grand Rounds.
• Klimentidis, Y. C. (2014, February). Challenges in Analyzing Genetics of Complex Traits. UA Biostatistics Seminar.
• Klimentidis, Y. C. (2014, September). Type-2 Diabetes: When Genes Meet Lifestyle. UA Nutrition Seminar.
• Klimentidis, Y. C. (2013, May). Towards an improved prediction of genetic risk for type-2 diabetes. Invited Talk at NIDDK - Phoenix Branch. Phoenix, AZ.

Poster Presentations

• Klimentidis, Y. C. (2018, October). Genome-wide association study of the lipedema phenotype in the UK Biobank.. American Society of Human Genetics. San Diego, CA.
• Klimentidis, Y. C., Chen, Z., Arora, A., & Hsu, C. (2014, October). Association of physical activity with lower type-2 diabetes incidence is weaker in those with high genetic risk. American Society of Human Genetics Annual Meeting. San Diego, CA.
• Klimentidis, Y. C., Wineinger, N. E., Vazquez, A. I., & de los Campos, G. (2014, June). Multiple Metabolic-Related Genetic Risk Scores and Type-2 Diabetes Risk in Three Ethnic/Racial Groups. American Diabetes Association Scientific Sessions. San Franciscon, CA.
• Klimentidis, Y. C., Thompson, P., Klimecki, W. -., Hu, C. -., Wu, G., Bea, J., Nicholas, J. S., Allison, D., & Chen, Z. -. (2013, Fall). Genetic variants in CAPN3 and ACVR2B are associated with lean body mass in postmenopausal women. The American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting. Baltimore, MD.
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  Yann Klimentidis, Patricia Thompson, Walter T. Klimecki, Chengcheng Hu, Guanglin Wu, Jennifer Wright Bea, Skye Nicholas, CHARGE Consortium Musculoskeletal Working Group, Zhao Chen Genetic variants in CAPN3 and ACVR2B are associated with lean body mass in postmenopausal women. (poster presentation) The American Society for Bone and Mineral Research Annual Meeting, Oct 2-7, 2013. Baltimore, Maryland USA.
• Klimentidis, Y. C., Vazquez, A., de los Campos, G., & Allison, D. (2013, November). High-dimensional genetic prediction of type-2 diabetes susceptibility.. American Society of Human Genetics.