Manichaikul Ani, Rich Stephen S, Allison Matthew A, Guagliardo Nick A, Bayliss Douglas A, Carey Robert M, Barrett Paula Q
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.).
Hypertension. 2016 Aug;68(2):356-64. doi: 10.1161/HYPERTENSIONAHA.116.07564. Epub 2016 Jun 13.
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.
血压（BP）是一种复杂性状，是遗传和环境决定因素相互作用的结果。先前的研究表明，TASK-1通道整体缺失的小鼠血压升高，同时醛固酮生成存在多种失调。在人类中，对约10万名欧洲、东亚和南亚血统个体进行的全基因组关联研究发现，KCNK3（编码TASK-1的基因）中的一个单核苷酸多态性（SNP）与平均动脉压相关。本研究的动机基于以下假设：（1）KCNK3 SNP与血压及相关性状的关联扩展至黑人和西班牙裔；（2）KCNK3 SNP与血浆肾素活性和醛固酮水平相关。我们检查了动脉粥样硬化多族裔研究（MESA）中7840名参与者的基线血压测量值，以及1653名MESA参与者亚组中的醛固酮水平和血浆肾素活性。我们在MESA黑人中发现先前报道的KCNK3 SNP（rs1275988）与平均动脉压存在统计学显著关联（P = 0.024），在MESA西班牙裔中发现一个附近的SNP（rs13394970）与平均动脉压存在统计学显著关联（P = 0.031）。我们还发现了KCNK3的其他SNP与收缩压、平均动脉压和高血压的关联。我们还在MESA中确定了KCNK3 rs2586886与血浆醛固酮水平存在统计学显著关联，并证明小鼠中TASK-1通道的整体缺失会产生轻度醛固酮增多症，且与肾素降低无关。我们的结果表明，KCNK3基因的遗传变异可能导致血压变异以及不太严重的高血压疾病，其中醛固酮可能是多种致病因素之一。
