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

untranslated region of CRTH2showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P 5 0.003) ofSNP 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 independentpopulations, and demonstrated significant association of the 1544G–1651G haplotype with asthma in anAfrican American population (P 5 0.004), and in a population of Chinese children (P < 0.001). Moreover, inthe Chinese children the frequency of the 1651G allele in near-fatal asthmatics was significantly higherthan mild-to-moderate asthmatics (P 5 0.001) and normal controls (P < 0.001). The 1651G allele of SNPre545659 was also associated with a higher degree of bronchial hyperresponsiveness (P < 0.027).Transcriptional pulsing experiments showed that the 1544G–1651G haplotype confers a significantlyhigher level of reporter mRNA stability, when compared with a non-transmitted haplotype (1544C–1651A),suggesting that the CRTH2 gene on Chr. 11q is a strong candidate gene for asthma.INTRODUCTIONSusceptibility genes for asthma, a chronic and often debilitat-ing inflammatory disease, remain to be defined. Geneticmapping and candidate gene analyses have revealed sug-gestive evidence for linkage to a number of different chromo-somal regions and for association with several candidate genes(reviewed in 1). Evidence for a genetic contribution to risk forfatal or near-fatal asthma has also been suggested (2,3), but thegenetic basis is still unclear. These results have been generatedmostly from studies of Caucasian populations. Previously,a genome-wide scan and fine-mapping analyses providedevidence of linkage to chromosome (Chr.) 11q in AfricanAmericans, but not in Caucasian Americans, with a peakNPL score of 4.38 at marker D11S1337 (4,5). This peaklinkage region, spanning 5 Mb between the peak marker(D11S1337) and a centrometric marker (D11S1313), isknown to be gene rich and includes the CRTH2 gene.Human Molecular Genetics, Vol. 13, No. 21