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

Abstract

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.