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

Pubmed ID: 25187575

Pubmed Central ID: PMC4334838

Journal: Human molecular genetics

Publication Date: Jan. 15, 2015

Affiliation: Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.

MeSH Terms: Humans, Male, Adult, Female, Cardiovascular Diseases, Risk Factors, Cohort Studies, Gene Frequency, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, C-Reactive Protein, Plasma, Exome, Hepatocyte Nuclear Factor 1-alpha, Receptors, Interleukin-6, White People, Black or African American

Grants: HL080295, N01-HC-25195, N01HC25195, HHSN268200800007C, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100012C, HHSN268201200036C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, R01 AG023629, R01 HL080295, U01 HL080295, R56 AG023629, HHSN268201100001C, HHSN268201100002C, AG023629, N01 HC55222, RC2 HL102923, RC2 HL102926, RC2 HL102924, RC2 HL103010, RC2 HL102925, R01 HL059367, R01HL59367, R01 HL086694, R01HL087641, R01 HL087641, R01HL086694, RC2 HL-102926, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-103010, RC2 HL102419, 5RC2HL102419, U54 HG003273, R01 HL087652, R01 HL105756, HHSN268201000010C, N02-HL-6-4278, HHSN2682011000010C, R01HL071862, HL105756, U01DK085526, R25 CA094880, HL087652, F31 MH101905, R25CA094880, U01 DK085526, HHSN2682011000012C, R01 HL071862, UM1 CA182913, HHSN2682011000011C, HHSN268201100009I, HHSN268201100005G, HHSN268201100008I, HHSN268201100011I, HHSN268201100005I, HHSN268201100007I, HHSN268201100001I, HHSN268201100002I, HHSN268201000012C, R01 HL053560, S10 OD020069

Authors: Benjamin EJ, Hsu L, Psaty BM, Nickerson DA, Kim DS, Reiner AP, Rich SS, Jackson RD, Boerwinkle E, Wilson JG, Morrison AC, Bis JC, Fornage M, Schick UM, Auer PL, Lin H, Wei P, Pankratz N, Lange LA, Brody J, Stitziel NO, Carlson CS, Haessler J, Kooperberg C, Leal SM, 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, Kathiresan S, Peters U, Dupuis J, Gross MD

Cite As: 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 R, Nickerson DA, Kathiresan S, Peters U, Dupuis J, Wilson JG, Rich SS, Morrison AC, Benjamin EJ, Gross MD, Reiner AP, Cohorts for Heart and Aging Research in Genomic Epidemiology, National Heart Lung and Blood Institute GO Exome Sequencing Project. Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet 2015 Jan 15;24(2):559-71. Epub 2014 Sep 3.

Studies:

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.