COVID-19 severity: does the genetic landscape of rare variants matter?

Khadzhieva, Maryam B.; Gracheva, A. S.; Belopolskaya, Olesya B.; Kolobkov, Dmitry; Kashatnikova, Darya A.; Red'kin, Iu V; Kuzovlev, Аrtem; Grechko, Andrey V.; Salnikova, Lyubov E.

doi:10.3389/fgene.2023.1152768

Cited by 6 publications

(13 citation statements)

References 80 publications

(106 reference statements)

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“…Most of the variants identified in our study have allele frequencies (<1%). A growing number of studies support the key role of rare variants in causing susceptibility/severity to COVID-19 [12,[26][27][28][29][30][31][32].…”

Section: Discussionmentioning

confidence: 99%

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Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Waman,

Ashford,

Lam

et al. 2023

Preprint

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The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19.In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and its human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed impact of missense variants occurring in the protein-protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities to SARS-CoV-2 proteins, using 3D-complexes.We predicted a total of 26 affinity-enhancing variants from 14 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, RAE1, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed.Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.

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Section: Discussionmentioning

confidence: 99%

“…For example, rare variants in the Toll-like receptor 7 gene have been associated with increased severity and susceptibility of the COVID-19 [12]. Likewise, various studies including those by the GeNOMICC-ISARIC consortium suggests association of both common and rare variants with increased severity of COVID-19 [27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Waman,

Ashford,

Lam

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…In the rst case, strategies were directed from single-gene or candidate-pathway association studies, to genome-wide association studies (GWAS) and meta-analyses, attempting to build polygenic risk scores (The COVID-19 Host Genetics Initiative; The Severe Covid-19 GWAS Group; Genetics of Mortality in Critical Care initiative) 12 . In the second case, rare variants were identi ed through the implementation of next-generation sequencing (NGS) approaches, like sequencing of candidate-genes panels, as well as wholeexome and whole-genome sequencing experiments on large cohorts of patients and controls 12,13 . These studies were mostly performed by huge public consortia with different number of participating samples, and also by direct-to-consumer genetic companies (23andMe; https://www.23andme.com/; AncestryDNA; https://www.ancestry.com/dna/).…”

Section: Introductionmentioning

confidence: 99%

Rare host variants in ciliary expressed genes contribute to COVID-19 severity in Bulgarian patients

Kamenarova,

Kachakova-Yordanova,

Baymakova

et al. 2024

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit β, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.

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“…This is linked to other risk factors, the same as in the general population [ 15 ], as well as the severity of the causative variant [ 16 ] and the overall genetic background. Based on ideas from the omnigenic model of the heritability of complex traits, we recently showed that the cumulative effect of rare high-impact (HI) genetic variations across the exome is associated with the severity of COVID-19 [ 17 ]. The omnigenic hypothesis suggests that genes with regulatory variants in at least one disease-associated tissue may influence the overall risk of disease development [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, the total contribution of rare potentially pathogenic variants to the phenotype of severe COVID-19 was greater for PID genes than for other analyzed groups of genes potentially important in the context of severe infection development. We hypothesized that PID genes are enriched for core genes for a phenotype defined as severe COVID-19 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19

Khadzhieva,

Kolobkov,

Kashatnikova

et al. 2023

Biomolecules

Self Cite

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The development of severe COVID-19, which is a complex multisystem disease, is thought to be associated with many genes whose action is modulated by numerous environmental and genetic factors. In this study, we focused on the ideas of the omnigenic model of heritability of complex traits, which assumes that a small number of core genes and a large pool of peripheral genes expressed in disease-relevant tissues contribute to the genetics of complex traits through interconnected networks. We hypothesized that primary immunodeficiency disease (PID) genes may be considered as core genes in severe COVID-19, and their functional partners (FPs) from protein–protein interaction networks may be considered as peripheral near-core genes. We used whole-exome sequencing data from patients aged ≤ 45 years with severe (n = 9) and non-severe COVID-19 (n = 11), and assessed the cumulative contribution of rare high-impact variants to disease severity. In patients with severe COVID-19, an excess of rare high-impact variants was observed at the whole-exome level, but maximal association signals were detected for PID + FP gene subsets among the genes intolerant to LoF variants, haploinsufficient and essential. Our exploratory study may serve as a model for new directions in the research of host genetics in severe COVID-19.

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COVID-19 severity: does the genetic landscape of rare variants matter?

Cited by 6 publications

References 80 publications

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics

Rare host variants in ciliary expressed genes contribute to COVID-19 severity in Bulgarian patients

Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19

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