Date of Graduation

8-2014

Document Type

Dissertation (PhD)

Program Affiliation

Human and Molecular Genetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Eric Boerwinkle, PhD

Committee Member

Craig Hanis, PhD

Committee Member

James Hixson, PhD

Committee Member

Alanna Morrison, PhD

Committee Member

Oleh Pochynyuk, PhD

Abstract

Thiazide diuretics are a recommended first-line monotherapy for hypertension (i.e.SBP>140 mmHg or DBP>90 mmHg). Even so, diuretics are associated with adverse metabolic side effects, such as hyperlipidemia, hyperglycemia and hypokalemia which increase the risk of developing type II diabetes. This thesis used three analytical strategies to identify and quantify genetic factors that contribute to the development of adverse metabolic effects due to thiazide diuretic treatment. I performed a genome-wide association study (GWAS) and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and the Genetic Epidemiology of Responses to Antihypertensive (GERA) studies. Two SNPs (rs12279250 and rs4319515 (r2=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg/dl increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor (EGF)-like repeats and has been shown to represses adipogenic differentiation. No statistical significant association was found in the case of change in glucose or change in triglycerides in European-Americans in this study.

In order to increase the sample size and signal for the change in glucose, I performed a GWAS of longitudinal data and meta-analysis from 14 cohorts which are part of the CHARGE consortium. No statistically significant association was found. The lack of positive results in this analysis suggested that it is unlikely that there is a single common SNP with a large effect on the adverse reaction to the diuretic use. Therefore, we can speculate about the possible interaction of multiple variants each with modest effect sizes or the fact that rare variants are playing a greater part in this particular phenotype.

Finally, I performed a genome-wide association study and a Multi-Ethnic Meta-Analysis of change in blood potassium levels 718 European- and African-American hypertensive participants. SNPs rs10845697 (Bayes Factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes Factor= 5.258) on chromosome 8 near the Mitoferrin-1 gene reached GWAS significance (Bayes Factor > 5). These results, if replicated, suggested a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.

The main goal of this research was to explore first steps in developing hydrochlorothiazide personalize medicine in order to provide a lasting and positive impact on public health.

Keywords

Pharmacogenomics, Genomics, GWAS, hyperglycemia, hypokalemia, hydrochlorothiazide, GERA, PEAR