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Genetic Evidence of Causal Effect between C1q/TNF-Related Protein-1 and Atherosclerosis: a Bidirectional and
Juhong Pan1, Jia Huang1, Yueying Chen1
1Department of Ultrasound Imaging, Renmin Hospital of Wuhan University.
Insights
C1q/TNF-related protein-1 (CTRP1) causally influences cerebral, coronary, and other arterial atherosclerosis. This suggests CTRP1 is a potential therapeutic target for systemic atherosclerosis prevention and treatment.
Area of Science:
- Cardiovascular Genetics
- Metabolic Disease Research
- Genetic Epidemiology
Background:
- C1q/TNF-related protein-1 (CTRP1) has been linked to coronary artery disease.
- Understanding CTRP1's role in atherosclerosis at various vascular sites is crucial.
Purpose of the Study:
- To investigate the causal relationship between CTRP1 and atherosclerosis.
- To examine CTRP1's role across different vascular beds, including cerebral, coronary, and other arteries.
Main Methods:
- Utilized Mendelian randomization (MR) analysis with summary statistics from genome-wide association studies and the FinnGen biobank.
- Performed primary MR analysis, sensitivity analyses (Cochrane's Q, leave-one-out), and pleiotropy assessments (MR-Egger, MR-PRESSO).
- Validated findings using an Ischemic Stroke cohort and employed multivariable MR (MVMR) to assess independent effects.
Main Results:
- Confirmed causal effects of CTRP1 on cerebral (OR=1.31), coronary (OR=1.13), and other arterial atherosclerosis (OR=1.06).
- Validation cohort supported CTRP1's causal role in large-artery atherosclerosis (OR=1.10).
- Reverse MR analysis ruled out atherosclerosis causing CTRP1 changes; MVMR confirmed CTRP1's independent effect on atherosclerosis.
Conclusions:
- CTRP1 demonstrates a causal role in systemic atherosclerosis.
- CTRP1 emerges as a potential therapeutic target for preventing and treating atherosclerosis.
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.
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