Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study

Circ Cardiovasc Genet. 2014 Apr;7(2):178-88. doi: 10.1161/CIRCGENETICS.113.000173. Epub 2014 Mar 12.


Background: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.

Methods and results: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).

Conclusions: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

Keywords: C-reactive protein; continental population groups; ethnic groups; genetic pleiotropy; inflammation; molecular epidemiology; polymorphism, single nucleotide.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Asian People / genetics
  • Black People / genetics
  • C-Reactive Protein / metabolism*
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Hispanic or Latino / genetics
  • Humans
  • Indians, North American / genetics
  • Inflammation / blood
  • Inflammation / epidemiology
  • Inflammation / ethnology
  • Inflammation / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • United States / epidemiology
  • Young Adult


  • C-Reactive Protein

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