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

Hum Mol Genet. 2015 Jan 15;24(2):559-71. doi: 10.1093/hmg/ddu450. Epub 2014 Sep 3.

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.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Americans / genetics
  • C-Reactive Protein / genetics*
  • C-Reactive Protein / metabolism*
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / genetics
  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Exome*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Humans
  • Male
  • Plasma / chemistry
  • Polymorphism, Single Nucleotide
  • Receptors, Interleukin-6 / genetics
  • Risk Factors

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • IL6R protein, human
  • Receptors, Interleukin-6
  • C-Reactive Protein

Grant support