EXPRESS: Plasma metabolic signature of cardiovascular-kidney-metabolic syndrome and incident stroke: a nationwide prospective cohort study

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome has increasingly affected the middle-aged and elderly population. The relationship between CKM risk factors and stroke at metabolomic level and underlying genetic alterations remains unknown. METHODS: Elastic net regression was utilized to establish a metabolic signature indicative of CKM risk factors in 108,305 participants. Multivariable COX proportional hazard models were utilized to determine the association between CKM plasma metabolic signature and incident stroke. Causal relationships between metabolites and stroke were explored through mendelian randomization (MR) analysis and colocalization analysis. RESULTS: During a follow up of 13.94 years [Interquartile Range (IQR), 13.00 - 14.43], 3,881 incident stroke events were documented. 48 metabolites were identified to represent the metabolic process of CKM risk factors. After adjustment of demographic factors and CKM risk factors, the elevated metabolic signature was correlated with higher stroke incidence risks with hazard ratio of 1.075 [95% confidential intervals (CI), 1.001 - 1.154]. MR analysis identified 38 potential causal metabolites. In addition, colocalization analysis revealed LDLR and CELSR2 as two genetic targets. CONCLUSION: In general, this study identified a metabolic signature reflecting CKM risk factors is positively associated with stroke, while LDLR and CELSR2 might impact the metabolic process in CKM population at genetic level.