CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals

Abstract

Background: Disease-causing mutations in CACNA1D gene occur in aldosterone-producing adenomas and familial hyperaldosteronism. We determined whether single nucleotide polymorphisms in CACNA1D gene associate with higher aldosterone resulting in salt sensitivity of blood pressure (BP) and increased BP in men and women.

Methods: Data were obtained from the HyperPATH (International Hypertension Pathotypes) cohort, where participants completed a cross-over intervention of liberal and restricted sodium diets. Multi-Ethnic Genotyping Array identified 104 CACNA1D single nucleotide polymorphisms that met quality control. Single nucleotide polymorphism is rs7612148 strongly associated with systolic BP and was selected for study in 521 White participants in 3 scenarios ([1] hypertensives; [2] normotensives; [3] total population=hypertensives+normotensives) using multivariate regression analysis.

Results: In the total population and hypertensives, but not normotensives, risk allele carriers (CC, GC), as compared with nonrisk allele homozygotes (GG), exhibited higher salt sensitivity of BP and, on liberal sodium diet, higher systolic BP, lower baseline and angiotensin II-stimulated aldosterone, and lower plasma renin activity. On restricted sodium diet, BP was similar across genotypes, suggesting sodium restriction corrected/neutralized the genotype effect on BP. Because increased aldosterone did not seem to drive the increased salt sensitivity of BP and increased BP on liberal sodium diet, we assessed renal plasma flow. Renal plasma flow increase from restricted to liberal sodium diets was blunted in risk allele homozygotes in the total population and in hypertensives. A replication study in another cohort HyperPATH B (International Hypertension Pathotypes Cohort B) confirmed BP-genotype associations.

Conclusions: CACNA1D rs7612148 risk allele associated with increased BP and salt sensitivity of BP, likely due to an impaired ability to increase renal plasma flow in response to a liberal sodium diet and not to excess aldosterone.

Keywords: aldosterone; allele; blood pressure; renal plasma flow.

Figure 1.. Consort Diagram

Figure was created with BioRender.

Figure 2.. Systolic blood pressure and salt sensitivity of blood pressure in the 3 groups: Hypertensive + Normotensive (Total Population), Hypertensive, and Normotensive

SBP and SSBP are increased in CACNA1D risk allele carriers in the total population and in the hypertensive group, but not in the normotensive group. SBP indicates systolic blood pressure; SSBP, salt sensitivity of blood pressure.

Figure 3.. CACNA1D and blood pressure pathophysiology

When hypertensive CACNA1D risk allele carriers are exposed to an increase in dietary sodium, they exhibit a blunted increase in renal plasma flow. This leads to an impaired excretion of sodium, promoting an increase in blood volume, which results in a decrease in plasma renin activity and ALDO on a liberal sodium diet, an increase in systolic BP on a liberal sodium diet, and an increase in salt sensitivity of BP. Figure was created with BioRender.