Role of prostanoid DP receptor variants in susceptibility to asthma

N Engl J Med. 2004 Oct 21;351(17):1752-63. doi: 10.1056/NEJMoa031785.

Abstract

Background: Previous genetic studies have associated the region of the human genome (14q22.1) containing the gene for the prostanoid DP receptor (PTGDR) with asthma. A study of a mouse model suggests that the receptor is required for the expression of the asthma phenotype. Our associations of asthma with functional genetic variants of PTGDR link these observations.

Methods: We identified and evaluated combinations of genetic variants that influence PTGDR transcription for disease association in case-control studies of 518 white patients with asthma and 175 white controls and 80 black patients with asthma and 45 black controls.

Results: We identified four novel and two previously reported single-nucleotide polymorphisms (SNPs) in PTGDR and its vicinity. These define four common three-SNP haplotypes, which vary in their ability to support transcription of PTGDR and have distinct DNA-binding-protein affinity profiles. Individual PTGDR SNPs were significantly associated with asthma in both populations. Specific PTGDR haplotypes were significantly associated with a diagnosis of asthma in a large case-control study of whites (P=0.002); we confirmed these findings in a second population of blacks (P=0.01). Multivariate analysis of the haplotype combinations (diplotypes) demonstrated that both whites (odds ratio, 0.55; 95 percent confidence interval, 0.38 to 0.80; P=0.002) and blacks (odds ratio, 0.32; 95 percent confidence interval, 0.12 to 0.89; P=0.03) who had at least one copy of the haplotype with a low transcriptional efficiency had a lower risk of asthma than subjects with no copies of the haplotype.

Conclusions: Our functional and genetic findings identify PTGDR as an asthma-susceptibility gene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • African Continental Ancestry Group / genetics
  • Asthma / ethnology
  • Asthma / genetics*
  • DNA-Binding Proteins / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease* / ethnology
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Polymorphism, Single Nucleotide
  • Receptors, Immunologic
  • Receptors, Prostaglandin / genetics*
  • Sequence Analysis, DNA
  • Transcription, Genetic

Substances

  • DNA-Binding Proteins
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • prostaglandin D2 receptor