Genome-wide interaction studies reveal sex-specific asthma risk alleles

Hum Mol Genet. 2014 Oct 1;23(19):5251-9. doi: 10.1093/hmg/ddu222. Epub 2014 May 13.

Abstract

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Asthma / epidemiology
  • Asthma / genetics*
  • Chromosome Mapping
  • Continental Population Groups / genetics
  • Female
  • Gene Expression Regulation
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Reproducibility of Results
  • Sex Factors

Grant support