Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.

TitleRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.
Publication TypeJournal Article
Year of Publication2016
AuthorsYu, 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 AuthorsCHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*
JournalCirc Cardiovasc Genet
Volume9
Issue1
Pagination64-70
Date Published2016 Feb
ISSN1942-3268
KeywordsAlleles, 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.

DOI10.1161/CIRCGENETICS.115.001215
Alternate JournalCirc Cardiovasc Genet
PubMed ID26658788
PubMed Central IDPMC4771070
Grant ListR01 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

Similar Publications