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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.

SUBMITTER: Pandey RK

PROVIDER: S-EPMC8730738 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:SARS CoV-2, the causative agent for the ongoing COVID-19 pandemic, it enters the host cell by activating the ACE2 receptor with the help of two proteasesi.e., Furin and TMPRSS2. Therefore, variations in these genes may account for differential susceptibility and severity between populations. Previous studies have shown that the role of ACE2 and TMPRSS2 gene variants in understanding COVID-19 susceptibility among Indian populations. Nevertheless, a knowledge gap exists concerning the COVID-19 susceptibility of Furin gene variants among diverse South Asian ethnic groups. Investigating the role of Furin gene variants and their global phylogeographic structure is essential to comprehensively understanding COVID-19 susceptibility in these populations. We have used 450 samples from diverse Indian states and performed linear regression to analyse the Furin gene variant's with COVID-19 Case Fatality Rate (CFR) that could be epidemiologically associated with disease severity outcomes. Associated genetic variants were further evaluated for their expression and regulatory potential through various Insilco analyses. Additionally, we examined the Furin gene using next-generation sequencing (NGS) data from 393 diverse global samples, with a particular emphasis on South Asia, to investigate its Phylogeographic structure among diverse world populations. We found a significant positive association for the SNP rs1981458 with COVID-19 CFR (p < 0.05) among diverse Indian populations at different timelines of the first and second waves. Further, QTL and other regulatory analyses showed various significant associations for positive regulatory roles of rs1981458 and Furin gene, mainly in Immune cells and virus infection process, highlighting their role in host immunity and viral assembly and processing. The Furin protein-protein interaction suggested that COVID-19 may contribute to Pulmonary arterial hypertension via a typical inflammation mechanism. The phylogeographic architecture of the Furin gene demonstrated a closer genetic affinity of South Asia with West Eurasian populations. Therefore, it is worth proposing that for the Furin gene, the COVID-19 susceptibility of South Asians will be more similar to the West Eurasian population. Our previous studies on the ACE2 and TMPRSS2 genes showed genetic affinity of South Asian with East Eurasians and West Eurasians, respectively. Therefore, with the collective information from these three important genes (ACE2, TMPRSS2 and Furin) we modelled COVID-19 susceptibilityof South Asia in between these two major ancestries with an inclination towards West Eurasia. In conclusion, this study, for the first time, concluded the role of rs1981458 in COVID-19 severity among the Indian population and outlined its regulatory potential.This study also highlights that the genetic structure for COVID-19 susceptibilityof South Asia is distinct, however, inclined to the West Eurasian population. We believe this insight may be utilised as a genetic biomarker to identify vulnerable populations, which might be directly relevant for developing policies and allocating resources more effectively during an epidemic.

Project description:BackgroundDuring the first wave of the COVID-19 pandemic a high case fatality rate (CFR) was noticed worldwide including also Germany where the first European cases have been observed. The WHO recommended immediate intubation for patients with dyspnoea which has since been revised after reviewing the initial clinical outcome. The objective of this study is to analyze CFR and assess if there is an advantage of a more conservative management of COVID-19 induced hypoxemia.MethodsPCR confirmed COVID-19 infections and death counts were obtained for all German districts from 27 Jan 2020 until 15 Feb 2021 using official reports of Robert Koch Institute Berlin, Germany. A moving average CFRt was constructed by dividing disease related deaths two weeks after a given index day by the number of infections two weeks prior to that date. In addition to a local comparison also mortality outcomes in other German speaking countries were compared.ResultsThe mean CFR is estimated to be 2.92% based on 71.965 fatalities and 2.465.407 cases. There was a large regional scattering of CFRs across the German districts. Differences of the mortality pattern were observed also at state level and preserved across different sex and age groups while being largely independent of case numbers. Although Munich city had higher infection rates, more patients died during the first wave in Hamburg (OR 1.6, 95% CI 1.3-1.9) which was mirrored also by higher death risk at Hamburg intensive care units (OR 2.0, 95% CI 1.3-3.1). While the majority of Munich hospitals favoured a conservative management of hypoxemia including high flow nasal cannula (HFNC), Hamburg hospitals followed a more aggressive scheme of early mechanical ventilation (MV). Austria and Switzerland experienced higher CFRs than Germany during the first wave but after changing their treatment guidelines, both countries experienced lower CFRs during the second wave.ConclusionUsing retrospective public health data, different case fatality rates have been observed across Germany. A more conservative management of COVID-19 induced Adult Respiratory Distress Syndrome (ARDS) is justified also by epidemiological data.

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

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