KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension

Abstract

Blood pressure (BP) is a complex trait that is the consequence of an interaction between genetic and environmental determinants. Previous studies have demonstrated increased blood pressure in mice with global deletion of TASK-1 channels contemporaneous with diverse dysregulation of aldosterone production. In humans, genome-wide association studies (GWAS) in ~100,000 individuals of European, East Asian and South Asian ancestry identified a single nucleotide polymorphism (SNP) in KCNK3 (the gene encoding TASK-1) associated with mean arterial pressure (MAP). The current study was motivated by the hypotheses that (1) association of KCNK3 SNPs with BP and related traits extends to African Americans and Hispanics, and (2) KCNK3 SNPs exhibit associations with plasma renin activity (PRA) and aldosterone levels. We examined baseline BP measurements for 7,840 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), and aldosterone levels and PRA in a subset of 1,653 MESA participants. We identified statistically significant association of the previously reported KCNK3 SNP (rs1275988) with MAP in MESA African Americans (P=0.024) and a nearby SNP (rs13394970) in MESA Hispanics (P=0.031). We discovered additional KCNK3 SNP associations with systolic BP (SBP), MAP and hypertension. We also identified statistically significant association of KCNK3 rs2586886 with plasma aldosterone level in MESA and demonstrated that global deletion of TASK-1 channels in mice produces a mild-hyperaldosteronism, not associated with a decrease in renin. Our results suggest genetic variation in the KCNK3 gene may contribute to blood pressure variation and less severe hypertensive disorders in which aldosterone may be one of several causative factors.

Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans

“…KCNK3 encodes TASK-1, a member of the superfamily of potassium channel proteins, which functions primarily to control the resting membrane potential in many cell types. KCNK3 has been previously associated with mean arterial pressure and systolic blood pressure in GWAS of individuals of European and East Asian ancestry, and more recently in candidate gene analyses of African Americans and Hispanics [ 32 – 34 ]. The previously reported association is for a SNP located at 2kb upstream of KCNK3 (rs1275988) [ 32 , 33 ], which is in LD with rs2586886 in our Hispanic sample (r 2 = 0.70) and in 1000G EUR (r 2 = 0.94), and thus likely represent the same association.…”

TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications

“…Although the mutations of KCNJ5 resulting in increased Na + conductance are responsible for the clinical cases of primary hyperaldosteronism [93], pharmacological modulation of TASK-1 may also influence aldosterone production and the salt water balance. This idea is also supported by the primary hyperaldosteronism evoked by TASK-1 gene knockout in rodent models [66,94], and by the association of human TASK-1 (KCNK3) variants with hypertension and high plasma aldosterone levels [95]. In addition, knockout mice lacking TASK-1 channels are characterised by impaired carotid body chemoreceptor function [96].…”

Functional TASK-3–Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells

“…The combined deletion of TASK-1 and TASK-3 channels leads to excessive aldosterone overproduction and low renin in mice. By contrast, deletion of TASK-3 alone evokes mild-hyperaldosteronism and low renin 19 , whereas that of TASK-1 elicits mild-hyperaldosteronism without an accompanying suppression of renin 21 . Genetic variations in the human TASK-1 gene ( KCNK3 ) 21-23 are associated with measures of hypertension (rs1275988, rs13394970) and elevated plasma aldosterone (rs2586886), and KCNK3 mRNA is abundantly expressed in mouse and human adrenal cortex 24 .…”

“…By contrast, deletion of TASK-3 alone evokes mild-hyperaldosteronism and low renin 19 , whereas that of TASK-1 elicits mild-hyperaldosteronism without an accompanying suppression of renin 21 . Genetic variations in the human TASK-1 gene ( KCNK3 ) 21-23 are associated with measures of hypertension (rs1275988, rs13394970) and elevated plasma aldosterone (rs2586886), and KCNK3 mRNA is abundantly expressed in mouse and human adrenal cortex 24 . By contrast, the KCNK9 gene product, TASK-3, is principally expressed in the rodent adrenal cortex 25 , although low levels of message are detected in the human adrenal cortex 26 .…”