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Human Molecular Genetics Advance Access published online on September 2, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh279
© 2004 by Oxford University Press
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Article

Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability

Jing-Long Huang 1, Pei-Song Gao 2, Rasika A. Mathias 3, Tsung-Chieh Yao 1, Li-Chen Chen 1, Ming-Ling Kuo 4, Shih-Chang Hsu 2, Beverly Plunkett 2, Alkis Togias 2, Kathleen C. Barnes 2, Cristiana Stellato 2, Terri H. Beaty 5, Shau-Ku Huang 6*

1 Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Children's Hospital and Chang Gung University, Taoyuan, Taiwan
2 Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD
3 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD
4 Department of Microbiology and Immunology, Graduate Institute of Basic Sciences, Chang Gung University, Taoyuan, Taiwan
5 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
6 Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD

* To whom correspondence should be addressed. E-mail: skhuang{at}jhmi.edu.


  Abstract

The gene, CRTH2, encoding a receptor for prostaglandin D2 (PGD2), is located within the peak linkage region for asthma on chromosome (Chr.) 11q reported in African American families. Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3' untranslated region (3'-UTR) of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the1651G allele (p=0.003) of SNP rs545659. Haplotype analysis yielded additional evidence of linkage disequilibrium for the 1544G-1651G haplotype (p<0.001). Population-based case-control analyses were conducted in two independent populations, and demonstrated significant association of the 1544G-1651G haplotype with asthma in an African American population (p=0.004), and in a population of Chinese children (p<0.001). Moreover, in the Chinese children the frequency of the1651G allele in near-fatal asthmatics was significantly higher than mild-to-moderate asthmatics (p=0.001) and normal controls (p<0.001). The1651G allele of SNP re545659 was also associated with a higher degree of bronchial hyperresponsiveness (p<0.027). Transcriptional pulsing experiments showed that when compared to a non-transmitted haplotype (1544C-1651A), the 1544G-1651G haplotype confers a significantly higher level of reporter mRNA stability, suggesting that the CRTH2 gene on Chr. 11q is a strong candidate gene for asthma.


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