Genetic association of TMPRSS2 rs2070788 polymorphism with COVID-19 case fatality rate among Indian populations

Abstract

SARS-CoV-2, the causative agent for COVID-19, an ongoing pandemic, engages the ACE2 receptor to enter the host cell through S protein priming by a serine protease, TMPRSS2 . Variation in the TMPRSS2 gene may account for the disparity in disease susceptibility between populations. Therefore, in the present study, we have used next-generation sequencing (NGS) data of world populations from 393 individuals and analyzed the TMPRSS2 gene using a haplotype-based approach with a major focus on South Asia to study its phylogenetic structure and their haplotype sharing among various populations worldwide. Our analysis of phylogenetic relatedness showed a closer affinity of South Asians with the West Eurasian populations therefore, host disease susceptibility and severity particularly in the context of TMPRSS2 will be more akin to West Eurasian instead of East Eurasian. This is in contrast to our prior study on the ACE2 gene which shows South Asian haplotypes have a strong affinity towards West Eurasians. Thus ACE2 and TMPRSS2 have an antagonistic genetic relatedness among South Asians. Considering the significance of the TMPRSS2 gene in the SARS-CoV-2 pathogenicity, COVID-19 infection and intensity trends could be directly associated with increased expression therefore, we have also tested the SNPs frequencies of this gene among various Indian state populations with respect to the case fatality rate (CFR). Interestingly, we found a significant positive association between the rs2070788 SNP (G Allele) and the CFR among Indian populations. Further our cis eQTL analysis of rs2070788 shows that the GG genotype of the rs2070788 tends to have a significantly higher expression of TMPRSS2 gene in the lung compared to the AG and AA genotypes thus validating the previous observation and therefore it might play a vital part in determining differential disease vulnerability. We trust that this information will be useful in understanding the role of the TMPRSS2 variant in COVID-19 susceptibility and using it as a biomarker may help to predict populations at risk.

Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors

“…Interestingly, our study identified the G allele of the TMPRSS2 rs2070788 to be associated with the presence of post-COVID dyspnea. These results agree with previous findings showing that pulmonary TMPRSS2 expression is higher in people with GG genotype as compared to the AG and AA genotypes [ 36 ]. It is possible that some polymorphisms can be associated with specific post-COVID symptoms or that the effect of the investigated polymorphisms could induce a more severe COVID-19 phenotype, indirectly affecting the development of particular post-COVID symptoms.…”

The association of COVID-19 severity and susceptibility and genetic risk factors: A systematic review of the literature

“… ( Rahimi et al, 2021 ) TMPRSS2 rs2070788 India 393 COVID-19 patients rs2070788 may lead to worse clinical outcomes in COVID-19 patients. ( Pandey et al, 2022 ) TIRAP rs8177374 Netherlands 116 COVID-19 patients Carriers of rs8177374 could be associated with a significantly lower COVID-19 mortality. ( Traets et al, 2022 ) TMPRSS2 rs17854725/rs75603675/rs12329760/rs4303795 Iran 288 COVID-19 patients These polymorphisms were associated with increased risk of COVID-19 infection and severe disease.…”

The immunogenetics of COVID-19

“…Importantly, most of these association studies were conducted in European and East Asian cohorts, with a very few studies in South Asian cohorts (Srivastava et al 2020b ; Pandey et al 2022 ; Srivastava 2020a ; Ahmad et al 2021 ). This highlights the necessity of conducting more association studies in increasingly diverse populations.…”