Dysregulation of Aldosterone Secretion in African Americans Is Associated with Polymorphic Variants in Endothelin Gene (EDN1)

Presentation Number: OR10-6
Date of Presentation: April 3rd, 2017

Jia Wei Tan*1, Tina Gupta1, Jonathan S Williams2, Gail K. Adler1 and Gordon H Williams1
1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 2Brigham & Women's Hospital, Harvard Medical School, Boston, MA

Abstract

It has been repeatedly demonstrated that African Americans (AA) are more susceptible to cardiovascular (CV) disease than Caucasians, and increasing evidence suggests that inappropriate aldosterone (ALDO) secretion and increased CV risk are associated. Thus, we hypothesized that the increased CV risk in AA is secondary to a greater degree of ALDO dysregulation than seen in Caucasians. To test this hypothesis, we compared the state of ALDO regulation in AA and Caucasians in the HyperPATH cohort using a nested case control method [2:1:: Caucasians (n=510): AA (n=255)] and adjusted for BMI, age, gender and systolic blood pressure. We used a linear regression model with the dependent variable being ALDO/PRA ratio supine on a restricted Na+ intake (10 mmol Na+/day) and adjusted for the 4 variables above, cortisol, urine potassium and serum potassium. The ALDO/PRA was significantly greater (p<0.0001) in the AA than in the Caucasians. Thus, AA had inappropriately elevated ALDO level despite having lower PRA, cortisol and urinary potassium than Caucasians. We then investigated the effect of polymorphic variants in the endothelin gene (EDN1), a known regulator of ALDO secretion, on the ALDO/PRA ratio in the AA group versus Caucasian group. Linear regression analyses showed that minor allele carriers (SNP rs5370) had a significant association with an elevated ALDO/PRA ratio (p=0.015). Sub-group analyses demonstrated the minor allele carriers of the EDN1 have elevated ALDO/PRA in AA (G/G 17.0, G/T 28.7, T/T 33.8) compared to Caucasians (AA and G/G 10.4, G/T 12.2, T/T 11.4), and that this positive association was preserved in AA (p=0.048), but not in Caucasian (p=0.9). Further, there was a significant interaction between EDN1 minor allele and AA. (Coefficient: 11.4, 95%CI 2.5-20.3, p=0.012). The findings from our human studies support our hypothesis that AA have increased dysregulation of ALDO secretion as compared to Caucasians, and our genetic analyses suggest that this difference may be related to interaction of EDN1 genotype with ethnicity. These findings introduce a potential role for determining the EDN1 carrier status in high CV risk individuals, particularly among AA with subclincial hyperaldosteronism, as these patients may benefit from treatments such as mineralocorticoid-receptor antagonist that target the ALDO-dependent pathways.

 

Nothing to Disclose: JWT, TG, JSW, GKA, GHW