Functional variability of the adenosine A3 receptor (ADORA3) gene polymorphism in aspirin-induced urticaria.
BACKGROUND
To improve understanding of aspirin hypersensitivity, this study focused on adenosine as a noncyclooxygenase target molecule of aspirin. Adenosine may affect the release of histamine from cutaneous mast cells through a mechanism mediated by the adenosine A3 receptor.


OBJECTIVE
To investigate the genetic contribution of adenosine A3 receptor gene (ADORA3) polymorphisms in the pathogenesis of aspirin-induced urticaria (AIU) in a case-control association study in a Korean population.


METHODS
A case-control association study was performed in 385 patients with AIU and 213 normal controls from a Korean population. The functional variability of genetic polymorphisms in the ADORA3 gene was analysed in in vitro studies that included a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA), and ex vivo studies that included real-time polymerase chain reaction for mRNA expression in peripheral blood mononuclear cells and a histamine release assay.


RESULTS
A significant association of ADORA3 promoter polymorphism at -1050G/T was found with the phenotype of AIU. Patients with AIU showed higher frequency of the haplotype, ht1 (T(-1050) C(-564) ), compared with normal healthy controls. Moreover, ht1 (TC) was found to be a high-transcript haplotype by the luciferase activity assay, and a -564C allele-specific DNA binding protein was found by EMSA. Increased basophil histamine release was noted in subjects who had the high-transcript haplotype, ht1 (TC).


CONCLUSIONS
These results suggest that the high-transcript haplotype, ht1 (TC), of the ADORA3 gene may contribute to the development of cutaneous hyper-reactivity to aspirin, leading to the clinical presentation of AIU.
Kim
S-H
SH
Department of Allergy and Rheumatology, Ajou University School of Medicine, San-5, Woncheondong, Youngtonggu, Suwon 442-721, Korea.
Nam
E-J
EJ
Kim
Y-K
YK
Ye
Y-M
YM
Park
H-S
HS
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D001241:Aspirin / Q000009:adverse effects*; D001491:Basophils / Q000378:metabolism; D016022:Case-Control Studies; D004342:Drug Hypersensitivity / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D043704:Receptor, Adenosine A2B / Q000235:genetics; D043684:Receptor, Adenosine A3 / Q000235:genetics*; D014581:Urticaria / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D006632:Histamine; D001241:Aspirin