Association Between MUC13 Gene Polymorphisms and Exacerbations of Asthma Under the Influence of Cigarette Smoking

Acute exacerbation of asthma is often characterized by increased mucus production and hypersecretion. While mucins are believed to play a role in the pathogenesis and pathophysiology of airway diseases, no genetic studies on mucin genes have been conducted to date. We initially analyzed a genome-wide association dataset of 608 asthmatics, focusing on mucin gene polymorphisms. Subsequently, we conducted fine genotyping of the MUC13 gene in a separate cohort of 704 bronchial asthma patients monitored for over a year. Using generalized linear models and multiple logistic regression analyses, we evaluated the genetic associations of single nucleotide polymorphisms (SNPs) with the frequency of annual exacerbations and the likelihood of frequent exacerbations. Among 105 SNPs in 14 mucin genes analyzed, rs6765247 in MUC13 showed the most significant association with annual asthma exacerbation frequency. Fine genotyping revealed that individuals homozygous for the minor allele of rs6765247T>G had significantly more annual exacerbations compared to those with the common allele (mean ± SD; 0.94 ± 1.73 vs. 0.43 ± 1.02 and 0.35 ± 0.79, p = 0.001). The frequency of minor allele homozygotes was 3.2 times higher in frequent exacerbators than in nonfrequent exacerbators. The associations were particularly significant in smokers (interaction p = 0.009). These findings indicate that MUC13 is important in exacerbating asthma due to smoking and could be used as a marker to predict frequent exacerbations in smokers.