Abstract
The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified. Our aim was to evaluate whether common variants in these genes affect blood pressure in the general population. We studied 2037 adults from 520 nuclear families characterized for 24-hour ambulatory blood pressure and related cardiovascular traits. We genotyped 298 tagging and putative functional single nucleotide polymorphisms, achieving a median coverage of 82.4% across 11 candidate loci. Five polymorphisms in the KCNJ1 gene coding for the potassium channel, ROMK, showed associations with mean 24-hour systolic or diastolic blood pressure. The strongest association was with an intronic polymorphism, rs2846679, where the minor allele (frequency 16%) was associated with a -1.58 (95% CI -2.47 to -0.69) mm Hg change in mean 24-hour systolic blood pressure, after accounting for age, sex, and familial correlations (P=0.00048). Polymorphisms in the gene were also associated with clinic blood pressure and left ventricular mass as assessed by ECG Sokolow-Lyon voltage (P=0.0081 for rs675759). Associations with mean 24-hour systolic or diastolic blood pressure were also observed for variants in CASR, NR3C2, SCNN1B, and SCNN1G. The findings show that common variants in genes responsible for some Mendelian disorders of hypertension and hypotension affect blood pressure in the general population. Notably, variants in KCNJ1, which causes Bartter syndrome type 2, were strongly associated, potentially providing a novel target for intervention.
Highlights
The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified
Our principal finding was the association of several single nucleotide polymorphisms (SNPs) in the KCNJ1 gene, which codes for ROMK, the ATP-sensitive inwardly-rectifying potassium channel expressed in the thick ascending limb, with mean 24-hour systolic BP (SBP) and diastolic BP (DBP) as well as clinic blood pressure (BP)
The observations that variants in KCNJ1 were associated with several BP phenotypes and that the same variants were associated with an ECG marker of left ventricular mass in the anticipated direction for its relationship with BP add weight to the findings
Summary
The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified. The genetic bases of several rare monogenic forms of hypertension and hypotension have been elucidated (Table 1), providing important insight into the mechanisms of BP regulation, and in particular the central role of the kidney.[6] More common polymorphisms in the genes underlying these disorders are obvious candidates as potential contributors to BP variation in the general population. Mutations in the WNK1 gene cause pseudohypoaldosteronism type II (PHAII or Gordon syndrome), an autosomal dominant condition characterized by hypertension and hyperkalemia.[7] We have shown previously that common polymorphisms in WNK1 are associated with ambulatory BP in the general population.[4] a systematic interrogation of the effect of common variation in other genes underlying all the known familial disorders of hypertension and hypotension on BP has not hitherto been carried out. Our aim was to evaluate comprehensively the effect of common variants in these genes on BP in the general population
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