Two-Sample Mendelian Randomization Of Plasma Proteome And Sarcopenia

Background and purpose: Sarcopenia is a systemic progressive disorder characterized by loss of skeletal muscle mass and function with age,increasing the risk of adverse outcome events such as frailty,falls,a decline in physical function,and death.Currently,the etiology of sarcopenia is complex and unclear.Existing research evidence suggests that plasma proteins are closely related to sarcopenia,but the evidence is very limited.Two-sample Mendelian Randomization(TSMR)analysis has a unique advantage in exploring the etiology of complex diseases and has been widely used.Therefore,we used TSMR to analyze the causal association between plasma proteins and sarcopenia to explore putative causal proteins in sarcopenia,which provided a theoretical basis for the etiology research and drug target screening of sarcopenia.Methods: First,by using genome-wide association data from four blood protein studies and sarcopenia,we applied TSMR analysis to evaluate 310 plasma proteins as possible causal mediators of sarcopeniarelated traits: appendicular lean mass(ALM)and handgrip strength(right and left).Then,we performed a reverse TSMR analysis to rule out the reverse causal effects of sarcopenia on putative causal proteins.Finally,we performed a phenome-wide Mendelian randomization analysis(Phe-MR)of the identified putatively causal proteins for 784 diseases to test the possible side effects of these proteins on other diseases.Results: Five plasma proteins were identified as putatively causal proteins of sarcopenia.Specifically,leukocyte immunoglobulin-like receptor subfamily B member 2(LILRB2),asporin(ASPN),and contactin-2(CNTN2)may causally increase ALM,and ecto-ADP-ribosyltransferase4(ART4)and superoxide dismutase 2(SOD2)may causally decrease on the handgrip strength,respectively.Moreover,only ART4 of the five putative causal proteins detected reverse causality in grip strength,and the rest did not have reverse causality with sarcopenia traits.The Phe-MR analysis did not identify five putative causal proteins with side effects for other diseases.Conclusion: We systematically elucidate the causal relationship between plasma proteome and sarcopenia,identifies four putative sarcopenia causal proteins(LILRB2,ASPN,CNTN2 and SOD2),and evaluate their safety as potential drug targets for sarcopenia.This study provides new insights into the etiology and clinical treatment of sarcopenia.