Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males.
BACKGROUND
Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA).


METHODS
To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC).


RESULTS
Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04).


CONCLUSIONS
These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.
Kim
S-H
SH
Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea.
Oh
J-M
JM
Kim
Y-S
YS
Palmer
L J
LJ
Suh
C-H
CH
Nahm
D-H
DH
Park
H-S
HS
D000328:Adult; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology*; D001241:Aspirin / Q000276:immunology*; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D018077:Receptors, Leukotriene / Q000235:genetics* / Q000276:immunology; D012737:Sex Factors; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; C083169:leukotriene D4 receptor; D001241:Aspirin