Abstract
Aspirin-intolerant asthma (AIA) is a rare condition that is characterized by the development of bronchoconstriction in asthmatic patients after ingestion of non-steroidal anti-inflammatory drugs including aspirin. However, the underlying mechanisms of AIA occurrence are still not fully understood. To identify the genetic variations associated with aspirin intolerance in asthmatics, the first stage of genome-wide association study with 109,365 single nucleotide polymorphisms (SNPs) was undertaken in a Korean AIA (n = 80) cohort and aspirin-tolerant asthma (ATA, n = 100) subjects as controls. For the second stage of follow-up study, 150 common SNPs from 11 candidate genes were genotyped in 163 AIA patients including intermediate AIA (AIA-I) subjects and 429 ATA controls. Among 11 candidate genes, multivariate logistic analyses showed that SNPs of CEP68 gene showed the most significant association with aspirin intolerance (P values of co-dominant for CEP68, 6.0×10−5 to 4.0×10−5). All seven SNPs of the CEP68 gene showed linkage disequilibrium (LD), and the haplotype of CEP68_ht4 (T-G-A-A-A-C-G) showed a highly significant association with aspirin intolerance (OR = 2.63; 95% CI = 1.64–4.21; P = 6.0×10−5). Moreover, the nonsynonymous CEP68 rs7572857G>A variant that replaces glycine with serine showed a higher decline of forced expiratory volume in 1s (FEV1) by aspirin provocation than other variants (P = 3.0×10−5). Our findings imply that CEP68 could be a susceptible gene for aspirin intolerance in asthmatics, suggesting that the nonsynonymous Gly74Ser could affect the polarity of the protein structure.
Highlights
Aspirin, known as acetylsalicylic acid, has been used as an analgesic to relieve pain and fever, as well as an anti-inflammatory medication
In both of genome-wide and follow-up studies, the % declines of forced expiratory volume in 1s (FEV1) by aspirin provocation in Aspirinintolerant asthma (AIA) and AIA patients including intermediate AIA (AIA-I) patients were significantly increased compared to those of ATA controls (P,0.0001), indicating that this study could reflect an association between genetic polymorphisms and aspirin hypersensitivity in asthmatics
In subjects of 2nd stage, the values of predicted FEV1 % and PC20 methacholine were significantly lower in AIA patients than those of ATA controls, whereas the total IgE level was higher in cases than in controls (P,0.01)
Summary
Known as acetylsalicylic acid, has been used as an analgesic to relieve pain and fever, as well as an anti-inflammatory medication. Up to 20% of asthmatics are sensitive to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Aspirinintolerant asthma (AIA), as a unique clinical syndrome with acute bronchospasm after ingestion of aspirin or other NSAIDs, was first described in 1922 [1,2]. AIA is characterized by the triad of aspirin hypersensitivity, bronchial asthma, and chronic rhinosinusitis with nasal polyposis [3,4]. AIA progression from the upper to the lower respiratory tract is accompanied by persistent asthmatic symptoms with intense eosinophilic infiltration into the upper and lower airways. AIA generally begins at about 30 years of age and occurs more frequently in women [2,5]
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