Multisite chronic pain as a causal risk factor for coronary artery disease: findings from Mendelian randomization.

The potential consequences of the number of chronic pain sites (referred to multisite chronic pain) on the risk of cardiovascular diseases (CVDs) remain unclear. We attempted to investigate the causality of multisite chronic pain with CVDs and its possible causal mediators. Using summary genome-wide association statistics, two-sample Mendelian randomization (MR) analyses were performed to assess whether multisite chronic pain has a causal effect on the 3 CVDs including coronary artery disease, atrial fibrillation, and stroke. We then conducted MR mediation analyses to establish whether body mass index (BMI), smoking, and depression causally mediate any association. Genetic liability to multisite chronic pain was associated with increased risk of coronary artery disease (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.19-1.95 per one increase in the number of pain locations) but not with atrial fibrillation or stroke. We also found positive causal effects of multisite chronic pain on BMI, smoking, and depression and causal effects of BMI, smoking, and depression on coronary artery disease. In multivariable MR analyses, the excess risk of coronary artery disease was attenuated after adjusting for BMI (OR 1.43, 95% CI 1.05-1.93), smoking (OR 1.49, 95% CI 1.11-2.00), depression (OR 1.44, 95% CI 1.03-2.01), and 3 risk factors combined (OR 1.34, 95% CI 0.88-2.05). Our findings demonstrated that multisite chronic pain led to higher risk of coronary artery disease, which is partly mediated through BMI, smoking, and depression.