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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.

After the spill to humans, in the timeline of SARS-CoV-2, several positively selected variants have emerged. A phylogeographic study on these variants can reveal their spatial and temporal distribution. In December 2020, the alpha variant of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which has been designated as a variant of concern (VOC) by WHO, was discovered in the southeastern United Kingdom (UK). Slowly, it expanded across India, with a considerable number of cases, particularly in North India. The study focuses on determining the prevalence and expansion of the alpha variants in various parts of India. The genetic diversity estimation helped us understand various evolutionary forces that have shaped the spatial distribution of this variant during the peak. Overall, our study paves the way to understand the evolution and expansion of a virus variant.

The COVID-19 pandemic resulted in multiple waves of infection worldwide. The large variations in case fatality rate among different geographical regions suggest that the human susceptibility against this virus varies substantially. Several studies from different parts of the world showed a significant association of ABO blood group and COVID-19 susceptibility. It was demonstrated that individuals with blood group O are at the lower risk of coronavirus infection. To establish the association of ABO blood group in SARS-CoV-2 susceptibility, we for the first time analysed SARS-CoV-2 neutralising antibodies among 509 individuals, collected from three major districts of Eastern Uttar Pradesh region of India. Interestingly, we found neutralising antibodies in a significantly higher percentage of people with blood group AB (0.36) followed by B (0.31), A (0.22) and lowest in people with blood group O (0.11). We further estimated that people with blood group AB are at comparatively higher risk of infection than other blood groups. Thus, among the asymptomatic SARS-CoV-2 recovered people blood group AB has highest, whilst individuals with blood group O has lowest risk of infection.

The COVID-19 pandemic has resulted several waves of infection in many countries worldwide. The large variations in case fatality ratio among different geographical regions suggests that the human susceptibility against this virus varies substantially. Several studies from different parts of the world showed a significant association of ABO blood group and COVID-19 susceptibility. It was shown that individuals with blood group O are at the lower risk of coronavirus infection. To establish the association of ABO blood group in SARS-CoV-2 susceptibility, we for the first time analysed SARS-CoV-2 neutralising antibodies as well as blood groups among 509 random individuals from three major districts of Eastern Uttar Pradesh region of India.. Interestingly, we found neutralising antibodies in significantly higher percentage of people with blood group AB (0.36) followed by B (0.31), A (0.22) and lowest in people with blood group O (0.11). This indicates that people with blood group AB are at comparatively higher risk of infection than other blood groups. Further, in line to previous reports we too observed that people with blood group O have significantly decreased risk of SARS-CoV-2 infection. Thus, among the asymptomatic SARS-CoV-2 infected individuals with blood group AB has highest, whilst blood group O has lowest risk of infection.

Studies on host-pathogen interaction have identified human ACE2 as a host cell receptor responsible for mediating infection by coronavirus (Covid-19). Subsequent studies have shown striking difference of allele frequency among Europeans and Asians for a polymorphism rs2285666, present in ACE2. It has been revealed that the alternate allele (TT-plus strand or AA-minus strand) of rs2285666 elevate the expression level of this gene upto 50%, hence may play a significant role in SARS-CoV-2 susceptibility. Therefore, we have first looked the phylogenetic structure of rs2285666 derived haplotypes in worldwide populations and compared the spatial frequency of this particular allele with respect to the Covid-19 infection as well as case-fatality rate in India. For the first time, we ascertained a significant positive correlation for alternate allele (T or A) of rs2285666, with the lower infection as well as case-fatality ratio among Indian populations. We trust that this information will be useful to understand the role of ACE2 in Covid-19 susceptibility.

It was shown that the human Angiotensin-converting enzyme 2 (ACE2) is the receptor of recent coronavirus SARS-CoV-2, and variation in this gene may affect the susceptibility of a population. Therefore, we have analysed the sequence data of ACE2 among 393 samples worldwide, focusing on South Asia. Genetically, South Asians are more related to West Eurasian populations rather than to East Eurasians. In the present analyses of ACE2, we observed that the majority of South Asian haplotypes are closer to East Eurasians rather than to West Eurasians. The phylogenetic analysis suggested that the South Asian haplotypes shared with East Eurasians involved two unique event polymorphisms (rs4646120 and rs2285666). In contrast with the European/American populations, both of the SNPs have largely similar frequencies for East Eurasians and South Asians, Therefore, it is likely that among the South Asians, host susceptibility to the novel coronavirus SARS-CoV-2 will be more similar to that of East Eurasians rather than to that of Europeans.

Studies on host-pathogen interaction have identified human ACE2 as a host cell receptor responsible for mediating infection by coronavirus (COVID-19). Subsequent studies have shown striking difference of allele frequency among Europeans and Asians for a polymorphism rs2285666, present in ACE2. It has been revealed that the alternate allele (TT-plus strand or AA-minus strand) of rs2285666 elevate the expression level of this gene upto 50%, hence may play a significant role in SARS-CoV-2 susceptibility. Therefore, we have first looked the phylogenetic structure of rs2285666 derived haplotypes in worldwide populations and compared the spatial frequency of this particular allele with respect to the COVID-19 infection as well as case-fatality rate in India. For the first time, we ascertained a significant positive correlation for alternate allele (T or A) of rs2285666, with the lower infection as well as case-fatality rate among Indian populations. We trust that this information will be useful to understand the role of ACE2 in COVID-19 susceptibility.

It was shown that the human ACE2 is the receptor of recent coronavirus SARS-CoV-2 and variation in this gene may affect the susceptibility of a population. Therefore, we have analysed whole genome data of World populations focusing South Asia. Genetically, South Asians are more related with the West Eurasian populations rather than East Eurasians. Whereas, for this gene, unexpectedly South Asians are more closer to East Eurasians rather than West Eurasians. The phylogenetic analysis suggested that the majority of South Asian haplotypes are shared with the East Eurasians in the background of two unique event polymorphisms which are responsible for this attraction. The second SNP rs2285666 has marked difference among South Asian vs European/American. Hence, it is highly likely that among the South Asians, the host susceptibility to the novel coronavirus SARS-CoV-2 will be more similar to East/Southeast Asians rather than the Europeans.

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.