Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human

• DOI: 10.1007/s12041-020-01217-7
• Publication Date: 2020-06-09T06:18:18Z
• Authors: Sabyasachi Senapati; Shashank Kumar; Atul K. Singh; Pratibha Banerjee; Sandilya Bhagavatula
• Keywords: Epigenomics; SARS-CoV-2; Dipeptidyl Peptidase 4; Pneumonia, Viral; Serine Endopeptidases; Life Sciences; COVID-19; Genetic Variation; Virus Internalization; Polymorphism, Single Nucleotide; Linkage Disequilibrium; 3. Good health; Molecular Docking Simulation; Research Note; Betacoronavirus; Immunology of Infectious Disease; Spike Glycoprotein, Coronavirus; Genetics; Humans; Genetic Predisposition to Disease; Protein Interaction Domains and Motifs; Coronavirus Infections; Pandemics; Immunology and Infectious Disease

At present more than 200 countries and territories are directly affected by COVID-19 pandemic. Incidence and case fatality rate (CFR) are significantly higher among elderly individuals (age>60 yrs) and among type 2 diabetes and hypertension patients. Membrane receptor ACE2, membrane bound serine protease TMPRSS2 and membrane bound exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility in predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and four regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein-protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain), however, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26) were found not to involve physically in the said interaction. 5’ UTR variant rs13015258 (CD26) have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Over expression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetics.