Proteome-wide Mendelian Randomization Analysis Identified Potential Drug Targets for Myocardial Infarction

Abstract

AbstractBackgroundMyocardial infarction (MI) is a leading cause of global mortality. Finding effective drugs to treat MI is an urgent concern for clinicians. Proteome-wide Mendelian randomization (MR) analysis provides a new way to investigate invaluable therapeutic drug targets more efficiently.MethodsUsing a proteome-wide MR approach, we assessed the genetic predictive causality between thousands of plasma proteins and MI risk. First, by adopting several principles to judge genetic variants associated with plasma proteins and MI risk, we selected a series of suitable variants utilized as instrumental variables (IVs) for the latter Mendelian Randomization (MR) analysis. Second, we performed a proteome-wide MR analysis to select candidate proteins. Third, sensitivity tests including heterogeneity test, reverse causality test, and colocalization analyses were conducted to ensure the robustness of our selected protein. Last, we assessed the drugability of the identified potential drug targets for MI using databases including DrugBank, PharmGKB, and TTD.ResultsOf the identified IVs, 3,156 associated with 1,487 plasma proteins were validated. 15 proteins exhibited significant genetically predicted causal associations(P − value < 3.362∗10−5) with MI risk, including Plasmin, MSP, Apo B, TAGLN2, LRP4, C1s, Angiostatin, Apo C-III, PCSK9, ANGL4, FN1.4,Apo B, IL-6 sRa, SWAP70, FN, FN1.3. Sensitivity analyses pinpointed Plasmin and Angiostatin for heterogeneity and proteins MSP, Apo B, and Angiostatin for reverse causality effects. Colocalization analysis found several proteins sharing genetic variants with MI, notably Apo B, TAGLN2, LRP4, C1s, Apo C-III, PCSK9 and ANGL4. When the threshold was lowered to 0.7, additional variants SWAP70 could be contained. 7 potential drug targets for MI were identified: SWP70, TAGLN2, LRP4, C1s, Apo C-III, PCSK9, and ANGL4. Drugability assessment categorized these proteins into varying therapeutic potential categories, from successfully drugged targets to those only reported in the literature.ConclusionOur comprehensive study elucidated 7 promising drug targets offering profound insights into its molecular dynamics and presenting potential pathways for therapeutic interventions against MI.Clinical Perspective1) What Is New?★ The analysis of thousands of proteins has identified 7 proteins that have a potential causal role in myocardial infarction risk.★ Four of these ten proteins have drugs approved or in development that target them, and three 5 have not been previously reported to be associated with atrial fibrillation risk.2) What Are the Clinical Implications?★ The results of the present study demonstrate new potential drug/therapeutic targets for myocardial infarction.