Drug Target Mendelian Randomization Study For The Effect Of RAS Inhibitors On COVID-19 Susceptibility And Severity

Background:Coronavirus disease 2019(COVID-19)is a global pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.The clinical severity of COVID-19 ranges from asymptomatic to mild respiratory symptoms to critical conditions with severe complications involving multiple systems such as the cardiovascular and respiratory systems.The interaction between renin-angiotensin system(RAS)inhibitors and the development of COVID-19 disease has received considerable attention.RAS inhibitors may increase the expression of angiotensin converting enzyme 2(ACE2)in the respiratory tract,thereby promoting viral entry into host cells and increasing susceptibility to transmission,leading to severe life-threatening COVID-19 complications.On the other hand,RAS inhibitors may balance the RAS system,reduce lung inflammation and fibrosis,and improve patient symptoms.Currently,there is no consistent conclusion on the relationship between RAS inhibitors and susceptibility/severity of COVID-19.Drug target Mendelian randomization(MR)analysis uses genetic variants located within or near a gene encoding a drug target as instrumental variables to simulate downstream effects similar to the desired drug response(such as changes in gene expression,target protein,metabolite and biomarker levels)in order to explore the causal effect of drugs on clinical outcomes.Objective:A drug target MR approach was used to explore the causal relationship between 3 RAS inhibitors and COVID-19 susceptibility and severity outcomes.This will provide new research ideas and methods for the repurposing of COVID-19 drugs,provide a theoretical basis for the development of prevention and control strategies for COVID-19,and provide evidence to support drug management and treatment guidelines for COVID-19 patients.Methods:This study used a two-sample drug target MR analysis framework to explore the causal relationships between three RAS inhibitors and susceptibility/severity outcomes of COVID-19 at multiple levels of change in systolic blood pressure,target protein,and target gene expression levels using summary data from large-scale genome-wide association studies(GWAS)of systolic blood pressure,protein expression quantitative trait loci,and gene expression quantitative trait loci in European populations.This study included three RAS inhibitors:direct renin inhibitors(DRIs),angiotensin converting enzyme inhibitors(ACEIs),and angiotensin Ⅱ receptor blockers(ARBs),and used three strategies to screen for cis-drugtarget instrumental variables related to systolic blood pressure,target protein expression levels,and various tissue target gene expression levels respectively.Single-nucleotide polymorphisms(SNPs)located in and around target genes(± 500 kb)associated with systolic blood pressure(P<1 × 10-5),target protein expression(P<5× 10-8),and target gene expression(P<1 × 105)were screened as instrumental variables to proxy the therapeutic inhibition of these targets.COVID-19 outcome data were obtained from the COVID-19 Host Genetics Initiative(COVID-19 HGI)GWAS meta-analysis,including COVID-19 susceptibility phenotype,COVID-19 hospitalization phenotype,and COVID-19 severity phenotype.The MR analysis used inverse variance weighted(IVW)as the main analysis method,while six other MR analysis methods based on different model assumptions were used to check the consistency of the results.Cochran’s Q statistic of IVW,MR-Egger regression intercept test.MR-PRESSO global test,and leave-one-out method were used to assess heterogeneity and pleiotropy in MR causal estimates.Supplementary analysis examined the causal relationship between RAS inhibitors and ACE2 protein levels.Results:1.Drug target MR results using instrumental variables related to systolic blood pressure showed that ARBs were causally associated with a reduced risk of COVID-19 severity(IVW:OR=0.677,95%CI:0.486-0.944,P=0.0216).2.Drug target MR results using instrumental variables related to t target protein expression levels showed that ACEIs were causally associated with a reduced risk of COVID-19 severity(OR=0.885,95%CI:0.813-0.963,P=0.0046),DRIs were causally associated with a reduced risk of COVID-19 hospitalization(OR=0.625,95%CI:0.450-0.866,P=0.0048),and COVID19 severity(OR=0.538,95%CI:0.332-0.873,P=0.0121).3.Drug target MR results using instrumental variables related to target gene expression in different tissues showed that ACEIs had causal relationships with reduced risk of COVID-19 severity in lung tissue(OR=0.763,95%CI:0.624-0.933,P=0.0085),thyroid tissue(OR=0.573,95%CI:0.412-0.797,P=0.0009),and gastric tissue(OR=0.650,95%CI:0.504-0.839,P=0.0009);ARBs have a causal relationship with reduced risk of COVID-19 severity in lung tissue(OR=0.719,95%CI:0.534-0.969,P=0.0301).4.Supplementary analysis showed that none of the three RAS inhibitors were causally associated with ACE2 protein levels.Conclusion:This study used a drug target MR framework to evaluate the causal effect of three RAS inhibitors on COVID-19 outcomes using different drug target instrumental variable screening strategies.The results showed that RAS inhibitors are not causally associated with COVID-19 susceptibility but are causally associated with a reduced risk of COVID-19 severity.The results suggested that RAS inhibitors are safe to use in patients with COVID-19 and may reduce the risk of severe COVID-19.RAS inhibitors may be a potential drug for COVID-19 treatment and further research is needed to verify this.