Role of Postanoid DP Receptor Variants in Susceptibility to Asthma

T. Oguma, Lyle Palmer, E. Birben, L.A. Sonna, K. Asano, C.M. Lilly

Research output: Contribution to journalArticlepeer-review

127 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1752-1763
JournalNew England Journal of Medicine
Volume351
Issue number17
DOIs
Publication statusPublished - 2004

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