KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension.
Blood pressure (BP) is a complex trait that is the consequence of an interaction between genetic and environmental determinants. Previous studies have demonstrated increased BP in mice with global deletion of TASK-1 channels contemporaneous with diverse dysregulation of aldosterone production. In humans, genome-wide association studies 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. The current study was motivated by the hypotheses that (1) association of KCNK3 SNPs with BP and related traits extends to blacks and Hispanics, and (2) KCNK3 SNPs exhibit associations with plasma renin activity and aldosterone levels. We examined baseline BP measurements for 7840 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), and aldosterone levels and plasma renin activity in a subset of 1653 MESA participants. We identified statistically significant association of the previously reported KCNK3 SNP (rs1275988) with mean arterial pressure in MESA blacks (P=0.024) and a nearby SNP (rs13394970) in MESA Hispanics (P=0.031). We discovered additional KCNK3 SNP associations with systolic BP, mean arterial pressure, 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 that genetic variation in the KCNK3 gene may contribute to BP variation and less severe hypertensive disorders in which aldosterone may be one of several causative factors.
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.).
Ani
A
Manichaikul
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.).
Stephen S
SS
Rich
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.).
Matthew A
MA
Allison
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.).
Nick A
NA
Guagliardo
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.).
Douglas A
DA
Bayliss
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.).
Robert M
RM
Carey
From the Center for Public Health Genomics (A.M., S.S.R.), Biostatistics Section, Department of Public Health Sciences (A.M.), Department of Pharmacology (N.A.G., D.A.B., P.Q.B.), and Division of Endocrinology and Metabolism and Department of Medicine (R.M.C.), University of Virginia, Charlottesville; and Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.). pqb4b@virginia.edu.
Paula Q
PQ
Barrett
D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000235:genetics*; D001795:Blood Pressure Determination / Q000379:methods; D002140:California / Q000453:epidemiology; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006929:Hyperaldosteronism / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics; D006973:Hypertension / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*; D012083:Renin / Q000097:blood; D012307:Risk Factors
D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D000450:Aldosterone; D012083:Renin
African Americans; Hispanic; blood pressure; genetic association studies; hyperaldosteronism; hypertension