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

Role of prostanoid DP receptor variants in susceptibility to asthma.

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  • 1Combined Program in Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

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.

Copyright 2004 Massachusetts Medical Society.

PMID:
15496624
[PubMed - indexed for MEDLINE]
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