Association of TYK2 rs2304256 and rs12720270 single-nucleotide polymorphisms with COVID-19 severity

Abstract

Variability in COVID-19 disease severity suggests that host genetic factors influence immune responses and disease outcomes. Tyrosine kinase 2 (TYK2), encoded by the TYK2 gene, helps regulate immune responses and inflammation. However, the impacts of its variants on disease progression remain unclear. This study investigated the association between single-nucleotide polymorphisms (SNPs) in the TYK2 gene and COVID-19 severity. The study enrolled COVID-19 patients, with one group presenting severe symptoms and another group with mild symptoms. After DNA extraction, a specific region of the TYK2 gene was amplified and sequenced. Three SNPs were identified within the targeted region: rs2304255 (C>T), rs2304256 (C>A), and rs12720270 (G>A). Among these, rs2304256 (a missense variant) and rs12720270 (an intronic variant) showed significantly different allele frequencies between mild and severe COVID-19 groups. Computational predictions suggested that the identified missense mutations do not directly affect TYK2 protein function. However, expression quantitative trait locus analysis from the Genotype–Tissue Expression database indicated that rs2304256 and rs12720270 are associated with increased TYK2 expression. Furthermore, RNA sequencing data analysis suggested that these variants promote exon 8 inclusion in TYK2 mRNA. As higher levels of full-length TYK2 potentially cause cytokine over-signaling, SNPs rs2304256 and rs12720270 may contribute to exaggerated inflammatory responses during COVID-19, increasing disease severity.