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