Asthma exacerbation is influenced by genetic and environmental variables, although little is known about genetic changes based on smoking status. Therefore, a genome-wide association study (GWAS) and gene-level analysis based on smoking status were used to examine genetic variables linked with asthma exacerbations in smokers and nonsmokers, and the underlying processes were found.

A GWAS on the yearly frequency of asthma exacerbations was conducted in 420 nonsmoking and 188 smoking asthma patients. In addition, multi-marker Analysis of GenoMic Annotation (MAGMA) was used to assess gene-wise relationships, and Gene Ontology analysis was also done.

In the nonsmokers, 189 genes were associated with the yearly frequency of exacerbations (permutated P<0.001). F5, KLRC1, TAFA2, AIRE, IER3IP1, CHMP2A, IL31RA, ZNF497, DNMT3L, and MYT1L were the top ten genes (permutated P=1.0×10-4-1.7×10-4). In smoking asthmatics, 140 genes were related to asthma exacerbations, including KANK1, ZMYND12, ZNF34, ANXA11, VAV2, CCDC150, CCDC30, CATSPER3, ARMH2, and MPRIP (permutated P=9.23×10-5-5.50×10-4). The significant causative genes of asthma exacerbation (FDR q<0.05) were genes involved in the innate immune response in nonsmokers and the control of cell fate (including apoptosis) in smokers.

The findings implied new genetic possibilities for predicting asthma exacerbations and that asthma treatment techniques should consider smoking habits.