Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations
Authors: Pandey Rudra Kumar , Srivast Anshika , Mishra Rahul Kumar , Singh Prajjval Pratap , Chaubey Gyaneshwer 
Published: January 2023

Abstract
Background
SARS CoV-2, the causative agent for the ongoing COVID-19 pandemic, enters the host cell by activating the ACE2 receptor with the help of two proteases, i.e., Furin and TMPRSS2. Therefore, variations in these genes may account for differential susceptibility and severity between populations. Our previous studies have shown that ACE2 and TMPRSS2 gene variants are essential in understanding COVID-19 susceptibility among Indian populations. However, there is a knowledge gap regarding Furin gene variants and their phylogenetic structure among diverse Indian and South Asian ethnic groups and their impact on disease vulnerability, which needs to be investigated.
Material and methods
Considering the role of the Furin gene in the pathogenesis of SARS-CoV-2. We have used 450 samples from diverse Indian states and performed linear regression to analyse the Furin gene variant's allele frequency with COVID-19 CFR that could be epidemiologically associated with disease severity outcomes among populations. Associated genetic variants were further evaluated for their expression and regulatory potential through various Insilco analyses. Additionally, we examined the Furin gene architecture using next-generation sequencing (NGS) data from 393 diverse global samples, with a particular emphasis on South Asia, to investigate its phylogenetic makeup and the distribution of haplotypes among distinct global populations.
Results
We found a significant positive association for the rs1981458 with COVID-19 CFR among diverse Indian populations. Further QTL and other regulatory analyses showed various significant associations and positive regulatory roles of this SNP 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 phylogenetic architecture of the Furin gene demonstrated a closer genetic affinity between West Eurasian and South Asians. Therefore, it is worth proposing that in the context of 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 a contrasting genetic affinity of South Asian with East Eurasians and West Eurasians, respectively. Therefore, we modelled COVID-19 susceptibility for susceptibility of South Asia in between these two major ancestries with an inclination towards West Eurasians.
Conclusion
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 in COVID-19 and genetic structure and susceptibility for COVID-19 susceptibility of South Asia is inclined to West Eurasian population. We believe this insight may well 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.