Genetic mechanisms of aspirin hypersensitivity

Background: The clinical features of aspirin hypersensitivity include aspirin-intolerant asthma (AIA) and aspirin-induced acute or chronic urticaria/angioedema (AIAU or AICU). Since it is reported that leukotriene C4 synthase (LTC4S) promoter polymorphism is related to the imbalance of leukotriene synthetic pathways, several groups have investigated the molecular genetic mechanisms of AIA, including leukotriene-related genes. In AIU, recent studies suggest overproduction of cysteinyl leukotrienes (Cys-LTs) as one of the pathogenic mechanisms. We summarize recent findings on the molecular genetic mechanism of two representative phenotypes of ASA hypersensitivity, AIA and/or AIU. Methods/Data base: An analysis of own and literature-derived results of studies examining the genetic factors of aspirin hypersensitivity. Results: In AIA, the major pathogenic mechanism was known as overproduction of Cys-LTs with increased expression of cysteinyl leukotriene receptor 1. Association with genetic polymorphisms of CYSLTR1, PGE2, TXA2R, and CYSLTR2 were newly suggested in the pathogenesis of AIA. Several single nucleotide polymorphisms (SNPs) in the promoters of EP2, TBX21, COX-2, FcεRIβ, and TXA2R were also associated with AIA. In AIU, the genetic polymorphisms of ALOX5 and FcεRIα promoter were noted. A human leukocyte antigen (HLA) study suggested that DPB1*0301 is a strong genetic marker for AIA, and that HLA DRB1*1302 and DQB1*0609 are susceptible markers for AIU. Conclusion: Recent findings suggest that several key genes involved in leukotriene synthetic pathways could contribute to the development of ASA hypersensitivity. The identification of genetic markers for susceptibility to ASA hypersensitivity with supporting functional studies would help to further elucidate its pathogenic mechanism, which could make it possible to develop early diagnostic markers and provide therapeutic targets.