TXK Functional Variants Contribute to Asthma by Regulating Th1 and Th17 Cytokine Pathways

Introduction TXK is involved in the regulation of IFN-γ expression and T helper (Th)1 cell-mediated inflammation that underlies the development of neutrophilic asthma, however, its implication in asthma pathogenesis remains uncertain. This study aims to characterize the functional role of TXK single nucleotide polymorphism (SNP) contributing to asthma. Methods This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). Associations of TXK transcript expression with asthma phenotype, the transcript expression of IFN-γ and IL23A, and SNP genotype were assessed in peripheral blood mononuclear cell (PBMC) samples from n=658 individuals of the SMCSGES sub-cohort. Genetic associations of TXK SNPs with asthma were assessed in a case-control cohort of n=2407 individuals from the SMCSGES population. Functional effects of asthma-associated SNPs on TXK promoter activity were evaluated by in vitro promoter luciferase assay in THP-1 cells. Results We identified significant associations of upregulated TXK transcript expression with increased asthma risk (p<0.05) and the increased transcript expressions of both IFN-γ (p<0.0001) and IL23A (p<0.0001) in PBMC. A significant association between tag-SNP rs2661532 and TXK transcript expression was detected in PBMC: the allele "T" was significantly associated with a higher TXK expression than allele "C" (false discovery rate-adjusted p<0.05). The major allele "T" of rs2661532 is also significantly associated with a higher risk of asthma (p=0.0346, odds ratio=1.171, 95% confidence interval=1.011-1.357). The in vitro promoter luciferase assay showed the major alleles of rs6819804 and rs74513879 (tagged by rs2661532) are significantly associated with higher TXK promoter activity (p<0.05). Conclusion This study identified multiple TXK functional variants associated with asthma by regulating the transcript expression of TXK and downstream Th1 and Th17 cell-mediated inflammatory pathways. Our findings indicated the potential involvement of TXK functional variants in the development of neutrophilic asthma.