Title | Association of exome sequences with plasma C-reactive protein levels in >9000 participants. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Schick, 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 | Cohorts for Heart and Aging Research in Genomic Epidemiology, National Heart, Lung, and Blood Institute GO Exome Sequencing Project |
Journal | Hum Mol Genet |
Volume | 24 |
Issue | 2 |
Pagination | 559-71 |
Date Published | 2015 Jan 15 |
ISSN | 1460-2083 |
Keywords | Adult, Black or African American, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, 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, White People |
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 < 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. |
DOI | 10.1093/hmg/ddu450 |
Alternate Journal | Hum Mol Genet |
PubMed ID | 25187575 |
PubMed Central ID | PMC4334838 |
Grant List | 5RC2HL102419 / HL / NHLBI NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States F31 MH101905 / MH / NIMH NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States R25CA094880 / CA / NCI NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI 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 HHSN268201100001I / HL / NHLBI NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States RC2 HL102923 / 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 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 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 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 HL087652 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI 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 HHSN268201200036C / HL / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States HHSN268201100002C / WH / WHI NIH HHS / United States U01 DK085526 / DK / NIDDK NIH HHS / United States R01 HL071862 / HL / NHLBI NIH HHS / United States UM1 CA182913 / CA / NCI NIH HHS / United States RC2 HL-102925 / HL / NHLBI NIH 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 HHSN268201100002I / HL / NHLBI NIH HHS / United States HL080295 / HL / NHLBI NIH HHS / United States HHSN268201000012C / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 HL087641 / 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 N01 HC55222 / HC / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States |
Association of exome sequences with plasma C-reactive protein levels in >9000 participants.
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