Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma

In asthmatic airways, adenosine is a potent bronchoconstrictor with either pro- or anti-inflammatory effects depending on receptor interactions. While aspirin has been suggested to mediate adenosine action, the roles of adenosine and its receptors in aspirin-intolerant asthma (AIA) are not well-defined. Therefore, we evaluated associations between genetic polymorphisms of adenosine deaminase and the four adenosine receptors (A(1), A(2A), A(2B), and A(3)) with the AIA phenotype. The genes for adenosine deaminase (ADA) and the four adenosine receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3) were screened by direct sequencing, and 13 single nucleotide polymorphisms (SNPs) were selected among 23 polymorphisms. Using multivariate logistic regression analysis, we compared the frequencies of SNP genotypes and haplotypes among 136 patients with AIA, 181 patients with aspirin-tolerant asthma (ATA), and 183 normal individuals. We found significant differences between normal and patients with AIA in the ADORA1 SNP genotype frequencies for 1405C>T (P=0.001) and A102A (P=0.013). No other significant associations were detected for the other SNPs. In the haplotype analysis, ht[C-T-G] (P=0.003) and ht[A-C-G] (P=0.032) in ADORA1 and ht[A-T] in ADORA2 (P=0.013) were significantly associated with AIA. Genetic polymorphisms of adenosine receptors A(1) and A(2A) were associated with AIA, suggesting that adenosine might play a crucial role in the development of AIA through interactions with the A(1) and A(2A) receptors.