Plasma metabolites and risk of myocardial infarction:a bidir-ectional Mendelian randomization studyOA北大核心

BACKGROUND Myocardial infarction(MI)is a critical cardiovascular event with multifaceted etiology,involving several ge-netic and environmental factors.It is essential to understand the function of plasma metabolites in the development of MI and un-ravel its complex pathogenesis. METHODS This study employed a bidirectional Mendelian randomization(MR)approach to investigate the causal relations-hips between plasma metabolites and MI risk.We used genetic instruments as proxies for plasma metabolites and MI and con-ducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa.In addition,the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite(1400 metabol-ites)and MI(20,917 individuals with MI and 440,906 individuals without MI)susceptibility.Inverse variance weighted was the primary method for estimating causal effects.MR estimates are expressed as beta coefficients or odds ratio(OR)with 95%CI. RESULTS We identified 14 plasma metabolites associated with the occurrence of MI(P＜0.05),among which 8 plasma metab-olites[propionylglycine levels(OR = 0.922,95%CI:0.881-0.965,P＜0.001),gamma-glutamylglycine levels(OR = 0.903,95%CI:0.861-0.948,P＜0.001),hexadecanedioate(C16-DC)levels(OR = 0.941,95%CI:0.911-0.973,P＜0.001),pentose acid levels(OR = 0.923,95%CI:0.877-0.972,P = 0.002),X-24546 levels(OR = 0.936,95%CI:0.902-0.971,P＜0.001),glycine levels(OR = 0.936,95%CI:0.909-0.964,P＜0.001),glycine to serine ratio(OR = 0.930,95%CI:0.888-0.974,P = 0.002),and mannose to trans-4-hydroxyproline ratio(OR = 0.912,95%CI:0.869-0.958,P＜0.001)]were correlated with a decreased risk of MI,whereas the remaining 6 plasma meta-bolites[1-palmitoyl-2-arachidonoyl-GPE(16:0/20:4)levels(OR = 1.051,95%CI:1.018-1.084,P = 0.002),behenoyl dihydrosphin-gomyelin(d18:0/22:0)levels(OR = 1.076,95%CI:1.027-1.128,P = 0.002),1-stearoyl-2-docosahexaenoyl-GPE(18:0/22:6)levels(OR = 1.067,95%CI:1.027-1.109,P = 0.001),alpha-ketobutyrate levels(OR = 1.108,95%CI:1.041-1.180,P = 0.001),5-acetylamino-6-formylamino-3-methyluracil levels(OR = 1.047,95%CI:1.019-1.076,P＜0.001),and N-acetylputrescine to(N(1)+ N(8))-acetyl-spermidine ratio(OR = 1.045,95%CI:1.018-1.073,P＜0.001)]were associated with an increased risk of MI.Furthermore,we also observed that the mentioned relationships were unaffected by horizontal pleiotropy(P＞0.05).On the contrary,MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites(P＞0.05 for each comparison). CONCLUSIONS Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI,among wh-ich 13 plasma metabolites have not been reported previously.These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.