Missense variant rs75603675 within TMPRSS2 gene is associated with the increased risk of severe form of COVID-19

Host genetics among other factors play an important role in COVID-19 disease severity. TMPRSS2, a serine protease, facilitates the priming of the SARS-CoV-2 spike protein, which is essential for the virus to enter the host cell. Several studies had targeted the TMPRSS2 polymorphisms with respect to SARS-CoV-2 infection and COVID-19 disease severity. Initially, the Whole Exome Sequencing (WES) of 7 healthy individuals and 22 COVID-19 patients with different degrees of disease severity was conducted to find the mutational landscape in different genes. A total of 26 single nucleotide polymorphisms (SNPs) were identified of which six were within the exons of TMPRSS2 (four synonymous and two nonsynonymous variants) while the rest of the 20 SNPs were recognized within the flanking intronic regions of TMPRSS2 gene. The nonsynonymous SNPs, rs75603675 and rs12329760, were further evaluated for association with disease severity in a larger sample size of 120 individuals by PCR followed by Sanger sequencing. Neither allelic nor genotypic distributions of rs12329760 were significantly associated with COVID-19 disease severity. However, individuals harboring the A allele of rs75603675 was found to have higher risk of severe COVID-19 compared to the C allele [OR (95%CI): 1.95 (1.11–3.39), p = 0.019]. Also, the genotype A/A [OR (95%CI): 5.13 (1.00–26.38), p = 0.033] of rs75603675 was associated with increased risk of severe COVID-19 under the recessive genetic inheritance model. Although the impact of COVID-19 pandemic has waned due to vaccination and public health measures, continued research on the association of COVID-19 disease severity and infection susceptibility with host genetics is required to shed valuable insights on the future long-term health effects of COVID-19 and impact of new variants on different populations and enable implication of proper informed healthcare strategies during future public health crises.