Association of TMPRSS2 Gene Polymorphisms with COVID-19 Severity and Mortality: a Case-Control Study with Computational Analyses

Coronavirus disease 2019 (COVID-19) is a severe disease caused by a new variant of beta-coronavirus that first appeared in China. Human genetic factors, including polymorphisms, serve pivotal roles in the high transmission of SARS-CoV-2 and the stubbornly progressing sickness seen in a small but significant percentage of infected people; however, but these factors remain ill-defined. A total of 288 COVID-19 patients and 288 controls were genotyped for TMPRSS2 polymorphisms using both restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) and amplification refractory mutation system (ARMS)-PCR techniques. Different genotypes of TMPRSS2 polymorphisms were compared in terms of disease susceptibility and mortality. The statistical analysis showed that minor alleles of all studied variants statistically increased the risk of COVID-19, except for the rs75603675 C > A variant. The T allele of rs12329760 conferred an increased risk of COVID-19. Moreover, the AG/AC/TT/AG combination of genotypes significantly enhanced the risk of COVID-19 in our population. Different haplotypes of rs17854725/rs75603675/rs12329760/rs4303795 polymorphisms, including GACA, GACG, GATG, GATA, AATA, ACCG, ACTG, ACTA, GCCA, and GCTG, were found to be associated with increased risk of the disease (odds ratio > 1). Regarding the clinical and paraclinical characteristics, a statistically significant difference was found between non-severe and severe forms except for gender, platelet, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and underlying diseases. In addition, case genotypes of TMPRSS2 rs17854725 A > G, rs12329760 C > T, and rs4303795 A > G were significantly different regarding severe and non-severe forms of the disease (P-value < 0.001). Specifically, death was more frequent in carriers of the AG genotype of rs17854725 A > G (P-value = 0.022). Patients who carry the minor alleles of the four studied TMPRSS2 variants were rather vulnerable to COVID-19 infection. Our findings indicated that rs17854725 A > G (AA vs. AG and AA vs. GG), rs12329760 C > T (CC vs. CT and CC vs. TT), and rs4303795 A > G (AA vs. AG) genotypes of TMPRSS2 variations are associated with a more invasive disorder pattern. More studies on larger populations are needed to confirm our results.