Genetic liability to multi-site chronic pain increases the risk of cardiovascular disease

Background: Observational studies have shown associations between multi-site chronic pain (MCP) and cardiovascular disease. However, it remains unclear whether these associations are causal. Therefore, this study aimed to assess the causal associations between MCP and cardiovascular disease and identify possible mediators between them.Methods: A two-sample Mendelian randomisation analysis was applied in this study. The summary data for MCP were obtained from a genome-wide association study that included 387 649 individuals from the UK Biobank, whereas summary-level data for cardiovascular disease and its subtypes were obtained from relevant genome-wide association studies. Finally, summary-level data for common cardiovascular risk factors and inflammatory biomarkers were lever-aged to identify possible mediators.Results: Genetic liability to multi-site chronic pain is associated with higher risks for coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), and stroke, with a combined odds ratio (OR) of 1.537 (per site increment in MCP; 95% confidence interval [CI]: 1.271-1.858; P=0.0001) for CAD, 1.604 (95% CI: 1.277-2.014; P=0.0005) for MI, 1.722 (95% CI: 1.423-2.083; P<0.00001) for HF, and 1.332 (95% CI: 1.093-1.623; P=0.00001) for stroke. Genetic liability to MCP was found to be associated with mental disorders, smoking initiation, physical activity, BMI, and lipid metabolites. Multi-variable Mendelian randomisation suggested a mediating role for mental disorders, smoking initiation, physical activity, and BMI in the relationship between multi-site chronic pain and cardiovascular disease.Conclusions: Our findings provide new insights into the role of multi-site chronic pain in cardiovascular disease. Additionally, we identified several modifiable risk factors for reducing cardiovascular disease.