Publication Date:
2014-12-24
Description:
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 x 10 –6 ). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs ( P = 3.0 x 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- 2 rs7214 with higher CRP levels. At the exome-wide significance level ( P 〈 5.0 x 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 x 10 –4 ) and in retinoic acid receptor-related orphan receptor α ( RORA ) in AAs ( P = 1.7 x 10 –3 ) were associated with CRP levels at the candidate gene level ( P 〈 2.0 x 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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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