Genetic causality of circulating inflammatory proteins and plasma metabolites in coronary atherosclerosis.

[BACKGROUND] Coronary atherosclerosis is a leading cause of cardiovascular disease and death worldwide. Despite progress in understanding its pathogenesis, the roles of circulating inflammatory proteins and plasma metabolites are complex and not fully elucidated. Existing Mendelian randomization (MR) studies often target isolated biomarkers, lacking comprehensive and mechanistic insights. This study uses MR to clarify the genetic causal relationships between circulating inflammatory proteins, plasma metabolites, and coronary atherosclerosis, and to explore potential mediation pathways.

[METHODS] Two-sample MR identified causal associations, while mediation analysis assessed whether plasma metabolites mediate the effects of inflammatory proteins on coronary atherosclerosis. Sensitivity analyses included Cochrane's Q test and MR-Egger intercept.

[RESULTS] Our analysis identified 11 circulating inflammatory proteins and 102 plasma metabolites associated with coronary atherosclerosis. Additionally, the genetic variants associated with elevated levels of eukaryotic translation initiation factor 4E-binding protein 1 (OR = 1.0590, 95% CI: 1.0050-1.1170) were found to increase the risk of coronary atherosclerosis through modulation of octadecanedioate and octadecanedioylcarnitine (C18-DC) levels, while leukemia inhibitory factor receptor (OR = 0.9400, 95% CI: 0.8890-0.9930)-associated variants reduced its risk through modulation of campesterol levels. Mediation analyses revealed that octadecanedioate levels (Mediated pro-portion = 18.5%), C18-DC levels (Mediated proportion = 21.6%) and campesterol levels (Mediated proportion = 26.7%) mediated these effects.

[CONCLUSIONS] This study provides new insights into the genetic and metabolic mechanisms underlying coronary atherosclerosis, extending beyond traditional biomarkers. The findings highlight potential therapeutic targets of coronary atherosclerosis and related metabolic disorders. Key messages What is already known on this topic: Coronary atherosclerosis, a leading cause of cardiovascular disease, has been linked to inflammatory proteins and plasma metabolites. However, the complexity of these relationships, particularly the genetic and metabolic mechanisms underlying the disease, remains poorly understood. Existing studies have largely focused on individual biomarkers and their associations with atherosclerosis, lacking comprehensive assessments and insights into potential mediation pathways. What this study adds: This study utilizes Mendelian randomization to identify genetic causal relationships between 11 circulating inflammatory proteins and 102 plasma metabolites with coronary atherosclerosis. It provides novel insights into the mediation roles of metabolites like octadecanedioate, C18-DC, and campesterol in the disease's progression. How this study might affect research, practice, or policy: By uncovering genetic and metabolic pathways involved in coronary atherosclerosis, this study lays the groundwork for future therapeutic interventions targeting these pathways. It highlights potential biomarkers and novel therapeutic targets, offering a new perspective on prevention and treatment strategies for coronary atherosclerosis and related metabolic disorders.