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Genetic Epidemiology of Hypertension in Populations

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Genetic Epidemiology of Hypertension in Populations GENETIC EPIDEMIOLOGY OF HYPERTENSION IN POPULATIONS: APPLICATIONS OF MODIFIED METHODS by PRIYA BHATIA SHETTY, M.S. Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Xiaofeng Zhu, Ph.D. Department of Epidemiology and Biostatistics CASE WESTERN RESERVE UNIVERSITY January, 2014 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Priya Bhatia Shetty, candidate for the Doctor of Philosophy degree*. Xiaofeng Zhu, PhD Robert C. Elston, PhD Jing Li, PhD Nathan Morris, PhD September 6, 2013 *We also certify that written approval has been obtained for any proprietary material contained therein. 2 Dedication This dissertation is dedicated to my husband Manju and our children Suvan, Poppy, Jujubee, and Sayali. 3 TABLE OF CONTENTS List of Tables………………………………………………………………….…………..5 List of Figures…………………………………………………………………………….6 Abstract……………………………………………………………………….…………..7 Chapter 1. Background……………………………………………………...….…………9 Chapter 2. Specific Aims………..……………………………………………………….53 Chapter 3. Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping………………..60 Chapter 4. Novel variants for HDL-C, LDL-C and triglycerides identified from admixture mapping and fine-mapping analysis in families…...…………………………………….85 Chapter 5. Identification of admixture regions associated with risk of apparent treatment- resistant hypertension in African-Americans………..………………………………….117 Chapter 6. Discussion………………………………..………………………………....137 References………………………………………………………………………………142 4 List of Tables Chapter 1. Table 1. Genome-wide Association Studies of Hypertension………...……...40 Chapter 1. Table 2. Other Analysis Methods in the Genetic Analysis of Hypertension in Unrelated Subjects………………………………………………………………...……..51 Chapter 3. Table 1. Summary statistics…………………………………………...……..80 Chapter 3. Table 2. Results of gene-based multivariable regression models……..….….81 Chapter 3. Table 3. Results of gene-based multivariable regression models that were nominally significant at α equal to 0.05…………………………………………..….….82 Chapter 3. Table 4. Results of gene-based multivariable regression models using local ancestry for replication analysis………………………………………………………….84 Chapter 4. Table 1. Summary statistics………………………………………………...104 Chapter 4. Table 2. Regions suggested by admixture mapping……………………...…105 Chapter 4. Table 3. Significant fine-mapping results…………………………………..106 Chapter 5. Table 1. Summary statistics………………………………………………...133 Chapter 5. Table 2. Significant results from the admixture mapping analysis………....134 5 List of Figures Chapter 4. Figures 1a-1g. Quantile-Quantile plots of fine-mapping analysis in families……………………………………………………………………………….....107 Chapter 4. Figures 2a-2g. Combined analyses plots........................................................108 Chapter 4. Supplemental Figures 3-3g. Admixture mapping…………………………..110 Chapter 5. Figure 1. Admixture mapping in all patients………………………………..135 Chapter 5. Figure 2. Admixture mapping in patients taking 2 anti-hypertensive drugs..136 6 Genetic Epidemiology of Hypertension in Populations: Applications of Modified Methods Abstract by PRIYA BHATIA SHETTY Objective: Modified methods of analysis were applied in three studies of African- Americans to identify variants associated with blood pressure and to address missing heritability in genetic studies of hypertension. Methods: Three genetic epidemiology studies were conducted in African-American subjects in the National Heart, Lung and Blood Institute’s Family Blood Pressure Program. First, a candidate gene association study using gene scores was conducted in genomic regions that previously showed admixture association evidence for blood pressure and other cardiovascular traits. Second, admixture mapping analyses were conducted on the 22 autosomal chromosomes for blood pressure and lipids, followed by fine-mapping analyses of the suggestive admixture regions in families. Third, admixture mapping analyses were conducted for blood pressure in subjects treated with at least 2 anti-hypertensive medications, and the regions suggesting admixture evidence were followed up with fine-mapping analyses in families to identify variants associated with apparent treatment-resistant hypertension. Stratified analyses were conducted by number of drugs for phenotypes showing significant association results in all subjects. 7 Results: In the first study, CXADR and F2RL1 were associated with blood pressure and body-mass-index, respectively. Analysis of local ancestry suggested that other associated SNPs were present in these regions. In the second study, the admixture mapping analyses identified seven regions associated with blood pressure and lipids. In the fine-mapping analyses, 11 SNPs in 8 independent loci were identified for associations with lipids. In the third study, admixture regions on chromosomes 3 and 5 were identified for association with blood pressure in all treated subjects and in subjects taking two anti- hypertensive drugs, respectively. The regions included variants that were previously identified in a large blood pressure GWAS, and the results suggested that the variants were associated with treatment response, rather than blood pressure, in African- Americans. Conclusions: A number of novel and known genomic and genetic variants were identified for blood pressure and other cardiovascular phenotypes. The methods of analysis were modified to incorporate gene scores, two-stage study designs and fine-mapping association analyses in families, and these adaptations were key in addressing some of the missing heritability in the genetics of hypertension and other cardiovascular traits. 8 Chapter 1. Background Hypertension One-quarter of adults worldwide suffer from high blood pressure, and this is a major public health issue because hypertension is an important risk factor for cardiovascular disease and stroke [1, 2]. Hypertension (HTN) is defined as untreated systolic blood pressure greater than or equal to 140 mm Hg and/or untreated diastolic blood pressure greater than or equal to 90 mm Hg or taking medication to reduce high blood pressure [3, 4]. Systolic blood pressure (SBP) is the amount of arterial pressure present when the heart contracts and diastolic blood pressure (DBP) is the amount of arterial pressure present when the heart relaxes. Between 1999 and 2008, approximately 30% of adults in the United States suffered from high blood pressure and only one-third of hypertensive patients had adequate control of their blood pressure to below 140/90 mm Hg according to the National Health and Nutrition Examination Survey (NHANES) of 1999-2000 [4, 5]. Epidemiological analyses of hypertension data have shown that risk of hypertension varies by race and ethnicity, sex and age. Approximately 40% of non-Hispanic black adults in the United States had hypertension in 1999-2008, compared to 25-30% of non- Hispanic white adults and Mexican American adults in the U.S during the same time period [4]. An analysis of NHANES data from 2000-2006 also showed that non- Hispanic black hypertensive adults were 1.49 times more likely to have poorly controlled blood pressure than non-Hispanic white hypertensive adults (odds ratio 1.49, 95% confidence interval (1.12, 1.98)) [6]. In young adulthood, SBP tends to be higher in men than women until age 60, after which women experience a more rapid age-associated 9 increase in SBP than men [7]. After age 60, women have a higher SBP than men; however, DBP increases steadily with age until approximately 55 years for both sexes, and it often declines after this point [7]. Besides age and sex, one of the most important risk factors for hypertension is obesity; a 10 kg increase in weight is associated with a 3 mm Hg increase in SBP and a 2.3 mm Hg increase in DBP [8]. Most of the effects of obesity on hypertension are mediated through changes in cardiac output and peripheral vascular resistance in that blood pressure = cardiac output X systemic vascular resistance. Obesity results in increased blood volume and stroke volume, which lead to increased cardiac output. In addition, obesity causes increased peripheral vascular resistance through a number of mechanisms, including endothelial dysfunction, sleep apnea and the release of inflammatory cytokines, such as IL-6 and TNF-α, by adipocytes [8]. Both genetic and environmental factors are associated with variation in blood pressure. The heritability of hypertension has been estimated to range between 34% and 67% from family studies and twin studies [9-11]. Interestingly, SBP and DBP have also shown considerable variability in heritability estimates by sex, in that males have higher heritability estimates than females for both SBP and DBP [7, 12]. In addition to these points, other considerations for studying blood pressure phenotypes are the decisions of how to treat the phenotype for analysis, continuous as in SBP and DBP or dichotomous as in hypertension (yes or no), and how to effectively adjust for anti-hypertensive treatment in the analysis. For instance, increased statistical power might be available when treating blood pressure as a continuous trait compared to a categorical trait, but the normality requirements of statistical methods for continuous 10 variables (e.g., linear regression) may require an appropriate transformation. On the other hand, treating blood pressure as a dichotomous phenotype is favorable because
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