Lung expression of genes encoding SARS-CoV-2 cell entry molecules and antiviral restriction factors: interindividual differences are associated with age and germline variants
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Abstract
Germline variants in genes involved in SARS-CoV-2 cell entry (i.e. ACE2 and TMPRSS2 ) may influence the susceptibility to infection, as may polymorphisms in genes involved in the innate host response to viruses (e.g. APOBEC3 family). We searched for polymorphisms acting, in lung tissue, as expression quantitative trait loci (eQTLs) for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. No significant eQTLs were identified for ACE2 and TMPRSS2 genes, whose expression levels did not associate with either sex or age of the 408 patients whose non-diseased lung tissue was analyzed. Instead, we identified seven cis -eQTLs (FDR<0.05) for APOBEC3D and APOBEC3G (rs139296, rs9611092, rs139331, rs8177832, rs17537581, rs61362448, and rs738469). The genetic control of the expression of APOBEC3 genes, which encode enzymes that interfere with virus replication, may explain interindividual differences in risk or severity of viral infections. Future studies should investigate the role of host genetics in COVID-19 patients using a genome-wide approach, to identify other genes whose expression levels are associated with susceptibility to SARS-CoV-2 infection or COVID-19 severity.
Author summary
Identification of expression quantitative trait loci (eQTLs) has become commonplace in functional studies on the role of individual genetic variants in susceptibility to diseases. In COVID-19, it has been proposed that individual variants in SARS-CoV-2 cell entry and innate host response genes may influence the susceptibility to infection. We searched for polymorphisms acting, in non-diseased lung tissue of 408 patients, as eQTLs for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. Seven cis -eQTLs were detected for APOBEC3D and APOBEC3G genes, which encode enzymes that interfere with virus replication. No significant eQTLs were identified for ACE2 and TMPRSS2 genes. Therefore, the identified eQTLs may represent candidate loci modulating interindividual differences in risk or severity of SARS-CoV-2 virus infection.
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SciScore for 10.1101/2020.06.24.168534: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Raw data were log2-transformed and normalized using the robust spline normalization method implemented in the lumi Bioconductor package [24]. lumisuggested: (lumi, RRID:SCR_012781)After pre-processing, measured intensities for genes of interest were extracted and then merged after adjusting for batch effects using the ComBat function from the sva R Bioconductor package [ ComBatsuggested: (ComBat, RRID:SCR_010974)Bioconductorsuggested: (Bioconductor, RRID:SCR_006442)Genotype data were subjected to quality control using PLINK v1.90b6.16 [26] following the protocol described in [27]. PLINKsugges…SciScore for 10.1101/2020.06.24.168534: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Raw data were log2-transformed and normalized using the robust spline normalization method implemented in the lumi Bioconductor package [24]. lumisuggested: (lumi, RRID:SCR_012781)After pre-processing, measured intensities for genes of interest were extracted and then merged after adjusting for batch effects using the ComBat function from the sva R Bioconductor package [ ComBatsuggested: (ComBat, RRID:SCR_010974)Bioconductorsuggested: (Bioconductor, RRID:SCR_006442)Genotype data were subjected to quality control using PLINK v1.90b6.16 [26] following the protocol described in [27]. PLINKsuggested: (PLINK, RRID:SCR_001757)The resulting dataset was then converted to a tabular format with the option --recode A-transpose. eQTL analyses: To test whether gene expression in lung tissue varied with the genotype of SNPs, we carried out an eQTL analysis by standard additive linear regression model, using the MatrixEQTL package [28] in R environment, assuming that genotype has an additive effect on gene expression. MatrixEQTLsuggested: NoneLinkage disequilibrium data and minor allele frequencies in the different populations were retrieved from the Ensembl genome browser. Ensembl genome browsersuggested: (Ensembl Genome Browser, RRID:SCR_013367)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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