Genetic Evidence of Causal Effect between C1q/TNF-Related Protein-1 and Atherosclerosis: a Bidirectional and Multivariate Mendelian Randomization Study.

Aims: To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease.

Methods: Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane's Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors.

Results: Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR=1.31, CI:1.04-1.66; FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08-1.19; FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02-1.11; FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03-1.18; FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis.

Conclusion: CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.