Genetic polymorphisms in aspirin-intolerant chronic urticaria

Background: Aspirin (acetylsalicylic acid, ASA)-intolerant urticaria with angioedema (AIU), a major type of aspirin-related hypersensitivity in urticaria, can be classified into two groups, acute ASA-intolerant urticaria (AIAU) and chronic ASA-intolerant urticaria (AICU), according to the duration of the urticaria. The pathogenic mechanism of AICU is not well understood. Methods/Data base: We present here a review of the recent findings from AICU molecular genetic studies. Results: A previous study on human leukocyte antigen (HLA) genotypes suggested that the HLA alleles DRB1*1302 and DQB1*0609 may be genetic markers for ASA-induced urticaria/angioedema for both AIAU and AICU, and that they were significantly associated with the prevalence of serum-specific immunoglobulin E (IgE) to staphylococcal superantigens, particularly in AICU patients. A polymorphism study that examined four leukotriene-related genes, ALOX5, ALOX5AP, PTGS2, and LTC4S, found that two promoter polymorphisms of ALOX5 at -1708A>G and CysLTR1 at -634 C>T, but not LTC4S (-444A>C), were significantly different between the phenotypes of ASA-intolerant asthma and AICU, suggesting different contributions to the leukotriene pathway from two different pathogenic mechanisms. Another genetic polymorphism study in patients with AIU did not find any significant associations with HRH1, HRH2, or MS4A2. However, the FCER1A (-344 C>T) and HNMT (939 A>G) gene polymorphisms were significantly associated with the AICU phenotype, and their functional abnormalities with the different genotypes were confirmed by in vitro functional studies. Conclusions: The two HLA alleles DRB1*1302 and DQB1*0609 and the ALOX5, FCER1A, and HNMT gene polymorphisms may contribute to the pathogenic mechanism of AICU. Further studies on the genetic mechanisms of AICU are needed to elucidate its pathogenic mechanism and aid in the development of new therapeutic strategies.