Title | Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Yu, B, Pulit, SL, Hwang, S-J, Brody, JA, Amin, N, Auer, PL, Bis, JC, Boerwinkle, E, Burke, GL, Chakravarti, A, Correa, A, Dreisbach, AW, Franco, OH, Ehret, GB, Franceschini, N, Hofman, A, Lin, D-Y, Metcalf, GA, Musani, SK, Muzny, DM, Palmas, W, Raffel, L, Reiner, A, Rice, K, Rotter, JI, Veeraraghavan, N, Fox, E, Guo, X, North, KE, Gibbs, RA, van Duijn, CM, Psaty, BM, Levy, D, Newton-Cheh, C, Morrison, AC |
Corporate Authors | CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP* |
Journal | Circ Cardiovasc Genet |
Volume | 9 |
Issue | 1 |
Pagination | 64-70 |
Date Published | 2016 Feb |
ISSN | 1942-3268 |
Keywords | Alleles, Black People, Blood Pressure, Chloride Channels, Exome, Female, Gene Frequency, Humans, Hypertension, Male, Risk Factors, White People |
Abstract | BACKGROUND: Rare genetic variants influence blood pressure (BP).METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation. |
DOI | 10.1161/CIRCGENETICS.115.001215 |
Alternate Journal | Circ Cardiovasc Genet |
PubMed ID | 26658788 |
PubMed Central ID | PMC4771070 |
Grant List | R01 HL059367 / HL / NHLBI NIH HHS / United States N01 HC048049 / HC / NHLBI NIH HHS / United States R01 CA082659 / CA / NCI NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States HHSN268201000010C / HL / NHLBI NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States HHSN268201100001I / HL / NHLBI NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States RC2 HL102923 / HL / NHLBI NIH HHS / United States N01-HC-95162 / HC / NHLBI NIH HHS / United States UL1TR000124 / TR / NCATS NIH HHS / United States P30 ES010126 / ES / NIEHS NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States R01 NS042733 / NS / NINDS NIH HHS / United States N01 HC048050 / HC / NHLBI NIH HHS / United States N01 HC095170 / HC / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States 5RC2HL102419 / HL / NHLBI NIH HHS / United States P50 HL084946 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States N01 HC048047 / HC / NHLBI NIH HHS / United States F32 HL083714 / HL / NHLBI NIH HHS / United States RC2 HL102926 / HL / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States R00 HG004316 / HG / NHGRI NIH HHS / United States RC2 HL101779 / HL / NHLBI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States HHSN2682011000010C / / PHS HHS / United States UL1-RR-025005 / RR / NCRR NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States N01 HC095167 / HC / NHLBI NIH HHS / United States RC2 HL-102926 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States N01 HC048048 / HC / NHLBI NIH HHS / United States R21 HL077916 / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States HHSN268201100004I / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States N01-HC-95163 / HC / NHLBI NIH HHS / United States N01-HC-95168 / HC / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States U01 HL089897 / HL / NHLBI NIH HHS / United States HHSN268201100046C / HL / NHLBI NIH HHS / United States N01 HC095161 / HC / NHLBI NIH HHS / United States RC2 HL-102923 / HL / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States N01 HC095164 / HC / NHLBI NIH HHS / United States N01-HC-95159 / HC / NHLBI NIH HHS / United States HHSN268201300048C / HL / NHLBI NIH HHS / United States HHSN268201100003C / WH / WHI NIH HHS / United States N01 HC095172 / HC / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States N01 HC095166 / HC / NHLBI NIH HHS / United States HHSN268201000011C / HL / NHLBI NIH HHS / United States N01-HC-95165 / HC / NHLBI NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01 HC095160 / HC / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States N02HL64278 / HL / NHLBI NIH HHS / United States N01 HC095171 / HC / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States N01 HC095095 / HC / NHLBI NIH HHS / United States U01 HL089856 / HL / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States RC2 HL-102924 / HL / NHLBI NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States HHSN268201300049C / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States RC2 HL102924 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States R01 NS039987 / NS / NINDS NIH HHS / United States N01-HC-95169 / HC / NHLBI NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States HHSN271201100004C / AG / NIA NIH HHS / United States N01-HC-95164 / HC / NHLBI NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States N01HC95159 / HL / NHLBI NIH HHS / United States R01HL105756 / HL / NHLBI NIH HHS / United States UL1-TR-000040 / TR / NCATS NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States UL1 RR025014 / RR / NCRR NIH HHS / United States HHSN2682011000012C / / PHS HHS / United States HHSN268201300050C / HL / NHLBI NIH HHS / United States N01-HC-95160 / HC / NHLBI NIH HHS / United States R01AG023629 / AG / NIA NIH HHS / United States HHSN268201300047C / HL / NHLBI NIH HHS / United States HHSN268201100002C / WH / WHI NIH HHS / United States N01 HC095169 / HC / NHLBI NIH HHS / United States M01 RR007122 / RR / NCRR NIH HHS / United States N01 HC095165 / HC / NHLBI NIH HHS / United States RC2 HL-102925 / HL / NHLBI NIH HHS / United States R21 HL123677 / HL / NHLBI NIH HHS / United States R01HL087652 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States UL1 TR002319 / TR / NCATS NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States N01 HC095168 / HC / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States RC2 HL103010 / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States N01-HC-95161 / HC / NHLBI NIH HHS / United States UL1 TR000040 / TR / NCATS NIH HHS / United States HHSN268201300046C / HL / NHLBI NIH HHS / United States HHSN268201100003I / HL / NHLBI NIH HHS / United States U01 HG004738 / HG / NHGRI NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States HHSN268201100002I / HL / NHLBI NIH HHS / United States U01HL080295 / HL / NHLBI NIH HHS / United States N01 HC095163 / HC / NHLBI NIH HHS / United States HHSN268201000012C / HL / NHLBI NIH HHS / United States R01HL103612 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC95166 / HL / NHLBI NIH HHS / United States N01-HC-95166 / HC / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States N01 HC095162 / HC / NHLBI NIH HHS / United States R01 AG027058 / AG / NIA NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01 HR046002 / HR / NHLBI NIH HHS / United States HHSN268201100001C / WH / WHI NIH HHS / United States RC2 HL102925 / HL / NHLBI NIH HHS / United States HHSN268201100004C / WH / WHI NIH HHS / United States R01 HL068890 / HL / NHLBI NIH HHS / United States RC2 HL-103010 / HL / NHLBI NIH HHS / United States N01 HC095159 / HC / NHLBI NIH HHS / United States N01-HC-95167 / HC / NHLBI NIH HHS / United States R01HL120393 / HL / NHLBI NIH HHS / United States HHSN2682011000011C / / PHS HHS / United States R01 HL076285 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States |
Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.
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