Insights into genetic factors contributing to variability in SARS-CoV-2 susceptibility and COVID-19 disease severity

D’Antonio, Matteo; Arthur, Timothy D.; Nguyen, Jennifer P.; Matsui, Hiroko; D’Antonio‐Chronowska, Agnieszka; Frazer, Kelly A.

doi:10.1101/2021.05.10.21256423

Cited by 3 publications

(3 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most markers found by GWAS are single-nucleotide variations (SNVs) at noncoding sites that often act as cis-regulatory variants. Expression quantitative trait loci (eQTL) analysis ( 24 , 25 ) is often used to identify causal regulatory variants from GWAS, which also requires many samples besides being deeply influenced by interindividual differences ( 26 ). SARS-CoV-2 infection is known to promote imbalances in the expression of genetic variants across the human genome ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

et al. 2023

View full text Add to dashboard Cite

IntroductionCell entry of SARS-CoV-2 causes genome-wide disruption of the transcriptional profiles of genes and biological pathways involved in the pathogenesis of COVID-19. Expression allelic imbalance is characterized by a deviation from the Mendelian expected 1:1 expression ratio and is an important source of allele-specific heterogeneity. Expression allelic imbalance can be measured by allele-specific expression analysis (ASE) across heterozygous informative expressed single nucleotide variants (eSNVs). ASE reflects many regulatory biological phenomena that can be assessed by combining genome and transcriptome information. ASE contributes to the interindividual variability associated with the disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs.MethodsWe compared ASE profiles in the human lung cell lines Calu-3, A459, and H522 before and after infection with SARS-CoV-2 using RNA-Seq experiments.ResultsWe identified 34 differential ASE (DASE) sites in 13 genes (HLA-A, HLA-B, HLA-C, BRD2, EHD2, GFM2, GSPT1, HAVCR1, MAT2A, NQO2, SUPT6H, TNFRSF11A, UMPS), all of which are enriched in protein binding functions and play a role in COVID-19. Most DASE sites were assigned to the MHC class I locus and were predominantly upregulated upon infection. DASE sites in the MHC class I locus also occur in iPSC-derived airway epithelium basal cells infected with SARS-CoV-2. Using an RNA-Seq haplotype reconstruction approach, we found DASE sites and adjacent eSNVs in phase (i.e., predicted on the same DNA strand), demonstrating differential haplotype expression upon infection. We found a bias towards the expression of the HLA alleles with a higher binding affinity to SARS-CoV-2 epitopes.DiscussionIndependent of gene expression compensation, SARS-CoV-2 infection of human lung cell lines induces transcriptional allelic switching at the MHC loci. This suggests a response mechanism to SARS-CoV-2 infection that swaps HLA alleles with poor epitope binding affinity, an expectation supported by publicly available proteome data.

show abstract

Section: Introductionmentioning

confidence: 99%

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

et al. 2023

View full text Add to dashboard Cite

show abstract

“…In particular, the Single nucleotide polymorphism (SNP) rs11385942 is present on the chromosome 3 at 3p21.31 locus and spans the six gene-containing clusters and has been associated with respiratory failure in patients with COVID-19 ( 120 ). Hospitalization of patients with COVID-19 and the severity of the disease are associated with a different mutation, rs1886814, in the transcription factor FOXP4 ( 129 ). A candidate causal variant rs10774671, present in the splice region of OAS1 , has been linked with COVID-19 severity ( 130 ).…”

Section: Possible Modulators Of Covid-19 Severitymentioning

confidence: 99%

Cellular heterogeneity in disease severity and clinical outcome: Granular understanding of immune response is key

Khare

Pandey

2022

Front. Immunol.

View full text Add to dashboard Cite

During an infectious disease progression, it is crucial to understand the cellular heterogeneity underlying the differential immune response landscape that will augment the precise information of the disease severity modulators, leading to differential clinical outcome. Patients with COVID-19 display a complex yet regulated immune profile with a heterogeneous array of clinical manifestation that delineates disease severity sub-phenotypes and worst clinical outcomes. Therefore, it is necessary to elucidate/understand/enumerate the role of cellular heterogeneity during COVID-19 disease to understand the underlying immunological mechanisms regulating the disease severity. This article aims to comprehend the current findings regarding dysregulation and impairment of immune response in COVID-19 disease severity sub-phenotypes and relate them to a wide array of heterogeneous populations of immune cells. On the basis of the findings, it suggests a possible functional correlation between cellular heterogeneity and the COVID-19 disease severity. It highlights the plausible modulators of age, gender, comorbidities, and hosts’ genetics that may be considered relevant in regulating the host response and subsequently the COVID-19 disease severity. Finally, it aims to highlight challenges in COVID-19 disease that can be achieved by the application of single-cell genomics, which may aid in delineating the heterogeneity with more granular understanding. This will augment our future pandemic preparedness with possibility to identify the subset of patients with increased diseased severity.

show abstract

“…Most of the markers found by GWAS are single-nucleotide variations (SNVs) at noncoding sites that often act as cis-regulatory variants. Expression quantitative trait loci (eQTL) analysis (24,25) is often used to identify causal regulatory variants from GWAS, which also requires many samples, despite being deeply influenced by interindividual differences (26). SARS-CoV-2 infection is known to promote imbalances in the expression of genetic variants across the human genome (27).…”

Section: Introductionmentioning

confidence: 99%

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Francisco

Temerozo

Ferreira

et al. 2022

Preprint

View full text Add to dashboard Cite

Cell entry of SARS-CoV-2 causes genome-wide disruption of the transcriptional profiles of genes and biological pathways involved in the pathogenesis of COVID-19. Expression allelic imbalance is characterized by a deviation from the Mendelian expected 1:1 expression ratio and is an important source of allele-specific heterogeneity. Expression allelic imbalance can be measured by allele-specific expression analysis (ASE) across heterozygous informative expressed single nucleotide variants (eSNVs). ASE reflects many regulatory biological phenomena that can be assessed by combining genome and transcriptome information. ASE contributes to the interindividual variability associated with disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs. We compared ASE profiles in the human lung cell lines Calu-3, A459, and H522 before and after infection with SARS-CoV-2 using RNA-Seq experiments. We identified 34 differential ASE (DASE) sites in 13 genes (HLA-A, HLA-B, HLA-C, BRD2, EHD2, GFM2, GSPT1, HAVCR1, MAT2A, NQO2, SUPT6H, TNFRSF11A, UMPS), all of which are enriched in protein binding functions and play a role in COVID-19. Most DASE sites were assigned to the MHC class I locus and were predominantly upregulated upon infection. DASE sites in the MHC class I locus also occur in iPSC-derived airway epithelium basal cells infected with SARS-CoV-2. Using an RNA-Seq haplotype reconstruction approach, we found DASE sites and adjacent eSNVs in phase (i.e., predicted on the same DNA strand), demonstrating differential haplotype expression upon infection. We found a bias towards the expression of the HLA alleles with a higher binding affinity to SARS-CoV-2 epitopes. Independent of gene expression compensation, SARS-CoV-2 infection of human lung cell lines induces transcriptional allelic switching at the MHC loci. This suggests a response mechanism to SARS-CoV-2 infection that swaps HLA alleles with poor epitope binding affinity, an expectation supported by publicly available proteome data.

show abstract

Insights into genetic factors contributing to variability in SARS-CoV-2 susceptibility and COVID-19 disease severity

Cited by 3 publications

References 55 publications

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Cellular heterogeneity in disease severity and clinical outcome: Granular understanding of immune response is key

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Contact Info

Product

Resources

About