Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We therefore used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n=1,038) and eQTLGen (n=31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n=3,301) with COVID-19-associated loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). We found that the expression of 20 genes in lung and 31 genes in blood was associated with COVID-19. Of these genes, only three (LZTFL1, SLC6A20 and ABO) had been previously linked with COVID-19 in GWAS. The novel loci included genes involved in interferon pathways (IL10RB, IFNAR2 and OAS1). Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in MR analysis; increased plasma levels were associated with an increased risk of having COVID-19 and risk of severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigation. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.

Inhaled corticosteroids downregulate SARS-CoV-2-related gene expression in COPD: results from a RCT

RationaleChronic obstructive pulmonary disease (COPD) is a risk factor for severe COVID-19. Inhaled corticosteroids (ICS) are commonly prescribed for the prevention of acute exacerbations in people with COPD, but their use is associated with increased risk of respiratory infections. The effects of ICS on SARS-CoV-2 susceptibility or COVID-19 severity are currently unknown. ObjectivesTo determine the effects of ICS treatment on the bronchial epithelial cell expression of key SARS-CoV-2-related genes in volunteers with COPD. MethodsWe performed a randomized, open-label, parallel treatment trial of 12 weeks treatment with ICS in combination with long-acting beta-agonist (formoterol/budesonide 12/400 {micro}g twice daily or salmeterol/fluticasone propionate 25/250 {micro}g twice daily), or treatment with LABA only (formoterol 12 {micro}g twice daily), in volunteers with mild to very severe COPD. We obtained bronchial epithelial cell samples via bronchoscopy before and after treatment, and determined transcriptome-wide gene expression by RNA sequencing. Main Results63 volunteers were randomized to receive treatment. Compared to formoterol alone, formoterol/budesonide treatment decreased the expression of the SARS-CoV-2 receptor gene ACE2 and the host cell protease gene ADAM17. These genes were highly co-expressed with innate immune response genes, particularly those of the type I interferon and anti-viral response pathways, which also tended to decrease following ICS treatment. ConclusionsThis is the first randomized controlled trial to show that ICS affect the expression of key SARS-CoV-2-related genes in COPD. Their relation to important anti-viral response genes may have critical implications for SARS-CoV-2 susceptibility or COVID-19 severity in this vulnerable population.

Gene Expression Network Analysis Provides Potential Targets Against SARS-CoV-2

ABSTRACTBACKGROUND Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets.METHODS Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions.RESULTS ACE2 was in a module of 681 co-expressed genes; 12 genes with moderate-high correlation with ACE2 (r>0.3, FDR<0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 15 of these genes were enriched in the gene ontology biologic process ‘Entry into host cell’, and 53 TMPRSS2-correlated genes had known interactions with drug compounds.CONCLUSION Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may help to fast-track the development of COVID-19 therapeutics.Competing Interest StatementS.M. reports personal fees from Novartis and Boehringer-Ingelheim, outside the submitted work. W.T. reports fees to Institution from Roche-Ventana, AbbVie, Merck-Sharp-Dohme and Bristol-Myers-Squibb, outside the submitted work. M.B. reports research grants paid to University from Astra Zeneca, Novartis, outside the submitted work. D.D.S. reports research funding from AstraZeneca and received honoraria for speaking engagements from Boehringer Ingelheim and AstraZeneca over the past 36 months, outside of the submitted work.View Full Text

ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study

ObjectivesTo use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. DesignTwo-sample Mendelian randomization (MR) analysis. SettingSummary-level genetic association data. ParticipantsParticipants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants). Main outcomes and measuresLung ACE2 and TMPRSS2 expression and plasma ACE2 levels. ResultsThere were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4x10-4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes. ConclusionsThis study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification. Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. C_LIO_LISerine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor. C_LIO_LIExpression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19. C_LI What this study addsO_LIWe used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels. C_LIO_LIOur findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression. C_LIO_LIWe found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies. C_LI