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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Ursula M Schick
  • Paul L Auer
  • Joshua C Bis
  • Honghuang Lin
  • Peng Wei
  • Nathan Pankratz
  • Leslie A Lange
  • Jennifer Brody
  • Nathan O Stitziel
  • Daniel S Kim
  • Christopher S Carlson
  • Myriam Fornage
  • Jeffery Haessler
  • Li Hsu
  • Rebecca D Jackson
  • Charles Kooperberg
  • Suzanne M Leal
  • Bruce M Psaty
  • Eric Boerwinkle
  • Russell Tracy
  • Diego Ardissino
  • Svati Shah
  • Cristen Willer
  • Ruth Loos
  • Ruth Mcpherson
  • Kees Hovingh
  • Muredach Reilly
  • Hugh Watkins
  • Domenico Girelli
  • Pierre Fontanillas
  • Daniel I Chasman
  • Stacey B Gabriel
  • Richard Gibbs
  • Deborah A Nickerson
  • Sekar Kathiresan
  • Ulrike Peters
  • Josée Dupuis
  • James G Wilson
  • Stephen S Rich
  • Alanna C Morrison
  • Emelia J Benjamin
  • Myron D Gross
  • Alex P Reiner
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)559-571
JournalHuman Molecular Genetics
Volume24
Issue number2
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes