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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  &lt; 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  &lt; 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.

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