<italic>TXK</italic> Functional Variants Contribute to Asthma by Regulating Th1 and Th17 Cytokine Pathways.

INTRODUCTION

TXK regulates IFN-γ expression and T-helper (Th)1 cell-mediated inflammation that underlies the development of neutrophilic asthma; however, its implication in asthma remains uncertain. This study aimed to functionally characterize the role of TXK single nucleotide polymorphism (SNP) in the development of asthma.

METHODS

This study is part of an ongoing Singapore/Malaysia Cross-Sectional Genetics and Epidemiological Study (SMCSGES). In a SMCSGES sub-cohort (n = 658), we assessed the associations of TXK mRNA expression with asthma phenotype, SNP genotype, and the mRNA expression of IFN-γ and IL23A in peripheral blood mononuclear cell (PBMC). Genetic associations between TXK variants and asthma were investigated in a case-control sub-cohort of SMCSGES (n = 2,407). The functional roles of asthma-associated TXK variants in regulating 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. The major allele "T" of tag-SNP rs2661532 was significantly associated with increased TXK mRNA expression compared to the "C" allele (false discovery rate-adjusted p < 0.05). The "T" allele of rs2661532 was 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) resulted in higher promoter activity of the TXK gene (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. These findings suggested that TXK functional variants might be involved in the development of neutrophilic asthma.