Drug Target Mendelian Randomization Study On The Association Between Antihypertensive And Lipid-Lowering Drugs And Inflammatory Cytokines

Background:The inflammatory response is an important immune defense response of the organism.When tissue is injured by bacterial or viral infection,heat or chemical irritation,the body is induced to produce an inflammatory response to repair the injury site in order to enter a self-protective state.A normal inflammatory response is a manifestation of the body’s immunity and is beneficial to the body.Inflammatory cytokines play a key role in the inflammatory response in the body by activating the body’s neutrophils as well as inflammatory cells such as lymphocytes,which increase the endothelial permeability of blood vessels.Uncontrolled inflammatory reactions can lead to microcirculatory dysfunction and even,organ dysfunction,and in severe cases,for example,excessive activation of immune cells can lead to a systemic inflammatory syndrome with multi-organ dysfunction due to inflammatory cytokine storm.Especially in patients with underlying diseases,the onset of excessive inflammatory responses can accelerate disease progression and lead to tissue and organ damage,as well as multi-organ dysfunction syndromes.Hypertension and dyslipidemia,two important chronic diseases in the elderly,are both associated with chronic inflammation,and the long-term use of antihypertensive and lipid-lowering drugs may have an impact on the inflammatory response,and it is extremely important to pay attention to the safety of patients’ medications.Targeting key cytokines in the mechanism of inflammatory response and lowering their levels or inhibiting progressive elevation of their levels will help prevent excessive inflammatory response from damaging multiple organs in patients.Therefore,rational selection of antihypertensive and lipid-lowering drugs is an important guide to avoid excessive inflammatory responses in patients with chronic diseases accompanied by an underlying inflammatory state.To this end,the relationship between antihypertensive and lipid-lowering agents and various inflammatory cytokines needs to be urgently evaluated.Observational studies have shown an association between antihypertensive and lipid-lowering drug use and some inflammatory cytokines.However,it remains difficult to determine the causal associations of antihypertensive and lipid-lowering drugs with various inflammatory cytokines due to the variable methodology and sample sizes of epidemiological studies,and the vulnerability of observational studies to unknown confounding factors.Drug target Mendelian randomization(Drug target MR)is a method for inferring causal relationships between drugs and outcomes using genetic variants located within or near target genes as instrumental variables,and using the instrumental variables to cause downstream effects similar to those of drug interventions to mimic drug exposure.This provides methodological support for exploring the causal association of antihypertensive and lipid-lowering drugs with inflammatory cytokines.Objective:To investigate the causal association between antihypertensive and lipidlowering drugs and inflammatory cytokines using a drug-targeted MR approach,to assess the causal effect sizes and their directions,and to provide a scientific basis for the selection of antihypertensive and lipid-lowering drugs in patients with hypertension and dyslipidemia,in order to achieve effective prevention and treatment of excessive inflammatory responses while treating chronic underlying diseases.Methods:The study selected clinically used antihypertensive agents including angiotensin-converting enzyme inhibitors(ACEIs),angiotensin Ⅱ receptor antagonists(ARBs),and lipid-lowering agents including 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGcoA reductase,HMGCR)inhibitors,preprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors,and Nieman Pick Cl-like protein 1(NPC1L1)inhibitors.Twelve inflammatory cytokines that play an important role in the inflammatory response were identified based on previous studies.Using genome-wide association study(GWAS)and expression number locus pooled data from European populations,drug-targeted MR instrumental variables for exploratory,validation and complementary analyses were constructed for antihypertensive and lipid-lowering drugs.In the exploratory analysis,Inverse-variance weighted(IVW)was used as the main analysis method,and five other MR methods based on different modeling assumptions were used to verify the consistency of the results.And sensitivity analysis was conducted using the leave-one-out method,Cochran’s Q test,and MR-Egger intercept test to verify the robustness of the results.In the validation analysis,for statistically significant druginflammatory cytokine trait pairs,IVW was still used as the main analysis method and supplemented with five other MR methods based on different modeling assumptions to verify the consistency of the results.In further complementary analyses,the effect of gene expression levels of drug target genes in different tissues on inflammatory cytokines was explored.Results:1.Antihypertensive drugs and inflammatory cytokines:Results of an exploratory analysis showed a causal association between ACEIs and reduced levels of the inflammatory cytokines Interleukin(IL)-1β,Tumor Necrosis Factor(TNF)-α,and C-reactive protein(CRP).the effect estimate for ACEIs with IL-1β was-0.116(P=0.013);the effect estimate for ACEIs with TNFα was-0.188(P=1.92E-3);the effect estimates for ACEIs with CRP The effect estimate of ACEIs versus CRP was-0.022(P=0.038).Validation analysis further demonstrated a causal association between ACEIs and IL-1β,TNF-α,and CRP,respectively,and the causal effect estimates obtained by different MR methods were generally consistent.The results of the complementary analysis showed a causal association between reduced ACE gene expression levels and reduced levels of TNF-α and CRP in several tissues.2.Lipid-lowering drugs and inflammatory cytokines:results of an exploratory analysis showed a causal association between HMGCR inhibitors and reduced levels of the inflammatory cytokines monocyte chemoattractant protein(MCP)-1,macrophage inflammatory protein(MIP)-1β,TNF-α,and interferon(IFN)-γ.The effect estimate for HMGCR inhibitors and MCP-1 was-0.298(P=6.26E-03);for HMGCR inhibitors and MIP1β was-0.302(P=0.032);HMGCR inhibitor with TNF-α with an effect estimate of-0.563(P=8.35E-04);and HMGCR inhibitor with IFN-γ with an effect estimate of-0.234(P=0.039).Results of exploratory analyses showed a causal association between PCSK9 inhibitors and reduced levels of the inflammatory cytokines IL-1β and IL-6,with an effect estimate of-0.255(P=0.017)for PCSK9 inhibitors versus IL-1β;and-0.271(P=0.003)for PCSK9 inhibitors versus IL-6.The validation analysis further demonstrated that HMGCR inhibitors were causally associated with MCP-1,MIP-1β,TNF-α and IFN-γ,respectively,and PCSK9 inhibitors were causally associated with IL-1β and IL-6,respectively,and the causal effect estimates obtained by different MR methods were generally consistent.The results of the complementary analysis showed that reduced HMGCR gene expression levels in skeletal muscle tissues were causally associated with reduced levels of MIP-1β,TNF-α and IFN-γ.Reduced PCSK9 gene expression levels in whole blood were causally associated with reduced IL-1β levels.Conclusion:This study elucidated the causal relationship between commonly used antihypertensive and lipid-lowering drugs and inflammatory cytokines by a drug-targeted Mendelian randomization approach.The results showed that the antihypertensive drugs ACEIs could reduce IL-1β,TNF-α,and CRP levels,and the lipid-lowering drugs HMGCR inhibitors could reduce MCP-1,MIP-1β,TNF-α,and IFN-γ levels,and the lipid-lowering drugs PCSK9 inhibitors could reduce IL-1β and IL-6 levels.This provides evidence for a causal association of different antihypertensive and lipid-lowering agents with inflammatory cytokines,but the mechanisms and details of which need to be further discovered.