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Association of exome sequences with plasma C-reactive protein levels in >9000 participants.

Wednesday,2015-03-04 14:08 America/Los_Angeles — zdrager
TitleAssociation of exome sequences with plasma C-reactive protein levels in >9000 participants.
Publication TypeJournal Article
Year of Publication2015
AuthorsSchick, UM, Auer, PL, Bis, JC, Lin, H, Wei, P, Pankratz, N, Lange, LA, Brody, J, Stitziel, NO, Kim, DS, Carlson, CS, Fornage, M, Haessler, J, Hsu, L, Jackson, RD, Kooperberg, C, Leal, SM, Psaty, BM, Boerwinkle, E, Tracy, R, Ardissino, D, Shah, S, Willer, C, Loos, R, Melander, O, McPherson, R, Hovingh, K, Reilly, M, Watkins, H, Girelli, D, Fontanillas, P, Chasman, DI, Gabriel, SB, Gibbs, R, Nickerson, DA, Kathiresan, S, Peters, U, Dupuis, J, Wilson, JG, Rich, SS, Morrison, AC, Benjamin, EJ, Gross, MD, Reiner, AP
Corporate/Institutional AuthorsCohorts for Heart and Aging Research in Genomic Epidemiology, National Heart, Lung, and Blood Institute GO Exome Sequencing Project
JournalHum Mol Genet
Volume24
Issue2
Pagination559-71
Date Published2015 Jan 15
ISSN1460-2083
KeywordsAdult, African Americans, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-alpha, Humans, Male, Plasma, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Risk Factors
Abstract<p>C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels. </p>
DOI10.1093/hmg/ddu450
Alternate JournalHum. Mol. Genet.
PubMed ID25187575
PubMed Central IDPMC4334838
Grant ListHHSN268201100012C / 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
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
R01 HL053560 / 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
N01HC85080 / HC / NHLBI NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01HL071862 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
U01DK085526 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R25 CA094880 / CA / NCI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
F31 MH101905 / MH / NIMH NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R25CA094880 / CA / NCI NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
R01 HL071862 / HL / NHLBI NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / / PHS HHS / United States
N01HC85082 / HL / NHLBI 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
RC2 HL103010 / HL / NHLBI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
N01 HC55222 / HC / NHLBI NIH HHS / United States
HHSN2682011000011C / / PHS HHS / United States

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