Date of Award

Spring 5-2020

Degree Name

Doctor of Philosophy (PhD)

Advisor(s)

MYRIAM FORNAGE PHD

Second Advisor

MICHAEL SWARTZ, PHD

Third Advisor

ERIC BOERWINKLE, PHD

Abstract

Multiple polymorphisms have shown associations with blood pressure (BP) levels and hypertension status, but the overall genetic effect on BP has been small and accounts for only a small fraction of the variation in population-wide BP characteristics. These weak associations of BP with genotype may not be attributable to the examining the “wrong” single nucleotide polymorphism (SNP) but may instead be the result of noisy BP phenotypes based on mmHg alone. Adding information from the underlying mechanisms of nutritional intake, reuptake, and excretion on BP may produce more informative BP phenotypes to study. To explore this complex relationship between diet, genes, and BP we chose 186 BP related SNPs from previous genome-wide association studies (GWAS) to test if sodium and potassium intake modify the existing BP-SNP relationship. Next, we tested if these BP related SNPs are associated with sodium and potassium intake. Lastly, we tested if the effects of sodium and potassium intake on BP are heterogeneous across race/ethnic groups. We combined data across four cohorts representing 3 racial ancestry groups (Black, White, and Hispanic participants) from the Population Architecture using Genomics and Epidemiology (PAGE) consortium to test our hypotheses. All analyses used participant-level data stratified by cohort and racial ancestry. Model coefficients were combined by meta analysis and assessed for effect heterogeneity across strata. We were unable to demonstrate experiment-wide significant interaction effect of dietary intake on the BP-SNP relationship but the closest nominally significant result indicated that the CASZ1 gene may play a part in the modulation of BP by both sodium and potassium among Hispanics. All nominally significant interactions between diet, gene, and BP showed heterogeneity of effects across racial ancestry groups. As for dietary associations with BP, we found a higher association between nutritional intake and BP among non-White participants which support current guideline recommendations of sodium sparing diets particularly in Black and Hispanic hypertensive patients. This study has provided more evidence of the heterogeneity of BP phenotypes among ancestry groups, particularly as they relate to nutritional intake and genetics. While dietary intake is likely an intermediate phenotype mediating gene-BP relationships, the effects are small and difficult to detect with highly variable intake measures. We suggest future studies focus on an alternate subset of SNPs from trans-ancestry BP association studies and employ a larger sample size in order to demonstrate significant interactions with dietary intake measures.

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