Abstract / Summary
Background: The current study investigated host genetic associations with disease severity in COVID-19 patients of South Asian origin and explored its molecular basis.
Methods: Covid-19 patients were stratified into disease severity groups based on the clinical and radiographic findings. Genomic DNA was extracted from peripheral blood samples. A two-step discovery and validation approach was utilized for genetic analysis. Whole-exome sequencing (WES) based variant prioritization was performed in a discovery cohort of severe disease patients followed by validation in an independent cohort. Bioinformatics analysis including data alignment, and annotation to the GRCh38 human reference genome was done by Ensembl VEP software. WES filtration pipeline utilizing predicted pathogenicity and population allele frequencies focused on the low-frequency and rare variants to filter out the variants of concern. Computational predictive tools and simulations were utilized for the structural and functional analysis of the identified high-risk SNP. Statistical analyses were done by SPSS version 24 and GraphPad Prism version 10.
Results: The missense variant rs199726033 of SVIL gene demonstrated the highest recurrence in the WES discovery cohort. The minor allele frequency (29.2%) was substantially higher than that reported for South Asians in the gnomAD v4 database (1.051%). A significant association of the mutant AC genotype of rs199726033 and disease severity was found in the validation cohort. Protein modeling and structural analysis localized the variant within a functionally conserved Gelsolin domain. Moreover, functional and pathway analysis of the SVIL variant indicates its potential role in actin filament remodeling relevant to COVID-19 related vasculopathy and cytoskeleton dynamics thus influencing host-viral interactions.
Conclusion: A SVIL missense variant is associated with disease severity and may influence host cytoskeletal processes relevant to COVID-19 severity.