Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability.
The gene, CRTH2, encoding a receptor for prostaglandin D(2) (PGD(2)), 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 of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G 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 the 1651G allele in near-fatal asthmatics was significantly higher than mild-to-moderate asthmatics (P = 0.001) and normal controls (P < 0.001). The 1651G allele of SNP re545659 was also associated with a higher degree of bronchial hyperresponsiveness (P < 0.027). Transcriptional pulsing experiments showed that the 1544G-1651G haplotype confers a significantly higher 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.
Huang
Jing-Long
JL
The Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan.
Gao
Pei-Song
PS
Mathias
Rasika A
RA
Yao
Tsung-Chieh
TC
Chen
Li-Chen
LC
Kuo
Ming-Ling
ML
Hsu
Shih-Chang
SC
Plunkett
Beverly
B
Togias
Alkis
A
Barnes
Kathleen C
KC
Stellato
Cristiana
C
Beaty
Terri H
TH
Huang
Shau-Ku
SK
D020413:3' Untranslated Regions; D001741:Black or African American / Q000208:ethnology / Q000235:genetics; D000483:Alleles; D000818:Animals; D044466:Asian People; D001249:Asthma / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics*; D011982:Receptors, Prostaglandin / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D018418:Th2 Cells / Q000378:metabolism*
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D007073:Immunoglobulin E; C036293:prostaglandin D2 receptor