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

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, RA, Nickerson, DA, Kathiresan, S, Peters, U, Dupuis, J, Wilson, JG, Rich, SS, Morrison, AC, Benjamin, EJ, Gross, MD, Reiner, AP
Corporate Authors,
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

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

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
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HHSN268201100008C / / PHS HHS / United States
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R25CA094880 / CA / NCI NIH HHS / United States
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HC-25195 / HL / NHLBI NIH HHS / United States
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HHSN268201100005C / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
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HHSN268201100006C / / PHS HHS / United States
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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
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