Sodium and Potassium Intake in Multiethnic Populations: Associations with Genes and Blood Pressure

Abstract

Over 80 million adults in the United States have hypertension, one of the leading risk factors for cardiovascular disease (CVD) and stroke. Sodium and potassium intake are essential dietary components, but excess sodium intake and insufficient potassium intake are established risk factors for hypertension and CVD. To improve and target interventions to reduce the burden of hypertension and CVD, it is critical to identify factors that influence sodium and potassium intake. The overarching goal of this dissertation is to provide insight into the genetics of sodium and potassium intake with high-quality measurement as well as the role of gene-by-sodium interactions underlying blood pressure variation in multiethnic populations. Aim 1 of the dissertation focuses on the identification of genomic regions associated with sodium intake, potassium intake, and sodium-to-potassium ratio in multiethnic populations. Using genome-wide genetic data imputed to the 1000 Genomes Project reference panel in five cohorts with European ancestry (N=7,363), one cohort with Asian ancestry (n=2,475), and one cohort with African Ancestry (n=1,246), we performed a genome-wide association study (GWAS) meta-analysis. We found a significant genetic locus, rs71639080, near the Fc fragment of IgG receptor genes (FCGR2B-FCGR2C- FCGR3A) on chromosome 1 from the meta-analysis of 24-hour urinary sodium excretion with a significance threshold of P < 5 X 10-8. Additionally, two genetic loci, rs77958157 on chromosome 5 and rs148459019 on chromosome 6, were significantly associated with sodium-to-potassium ratio. In Aim 2, we used sequence-kernel association methods to investigate gene-level associations from Aim 1 using both common and rare genetic variants. In addition, we evaluated whether the gene-level associations were modified by demographic factors (age ≥ 65 years, sex, and college education) and found significant interactions in the regions of genes TAPSAR1, CTC-228N24.1, RP11-433C9.2, and RP11-483H11.1 in a European American cohort. In Aim 3, we identified 12 genome-wide significant genetic loci (P < 5 X 10-8) through meta-analysis of a genome-wide gene-by-sodium intake interaction study on blood pressure measures using multiethnic cohort studies (N=6,020). One of the identified gene regions includes NKAIN2 (chromosome 6), which is associated with the regulation of sodium and potassium ion transporting within or between cells. Much research still remains to replicate and understand these initial findings in larger multiethnic populations to provide more insight into the underlying genetic variations and mechanisms by which these genomic regions are influencing the regulation of sodium and potassium intake, as well as blood pressure levels.