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Previous Volume 351:1752-1763 October 21, 2004 Number 17 Next

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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.

Source Information

From the Combined Program in Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (T.O., E.B., L.A.S., C.M.L.); Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Perth (L.J.P.); U.S. Army Research Institute of Environmental Medicine, Natick, Mass. (L.A.S.); and the Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo (K.A.).

Address reprint requests to Dr. Lilly at the Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis St., Thorn 826C, Boston, MA 02115, or at clilly{at}partners.org.

Full Text of this Article

Related Letters:

Prostanoid DP Receptor Variants and Asthma
Morita H., Nagai R., Deykin A., Lilly C. M., Palmer L. J.
Extract | Full Text | PDF  
N Engl J Med 2005; 352:837-838, Feb 24, 2005. Correspondence

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