GWAS reveals genetic basis of a predisposition to severe COVID-19 through in silico modeling of the FYCO1 protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is heavily reliant on its natural ability to "hack" the host's genetic and biological pathways. The genetic susceptibility of the host is a key factor underlying the severity of the disease. Polygenic risk scores are essential for risk assessment, risk stratification, and the prevention of adverse outcomes. In this study, we aimed to assess and analyze the genetic predisposition to severe COVID-19 in a large representative sample of the Russian population as well as to build a reliable but simple polygenic risk score model with a lower margin of error. Another important goal was to learn more about the pathogenesis of severe COVID-19. We examined the tertiary structure of the FYCO1 protein, the only gene with mutations in its coding region and discovered changes in the coiled-coil domain. Our findings suggest that FYCO1 may accelerate viral intracellular replication and excessive exocytosis and may contribute to an increased risk of severe COVID-19. We found significant associations between COVID-19 and LZTFL1, FYCO1, XCR1, CCR9, TMLHE-AS1, and SCYL2 at 3p21.31. Our findings further demonstrate the polymorphic nature of the severe COVID-19 phenotype.

The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.

Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995-2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia.