Exploring Sex Differences in Pain Manifestation of Coronary Artery Disease through Mendelian Randomization

Pain manifestation following coronary artery disease (CAD) disease differs between men and women. Here, we aimed to provide evidence favoring possible differences in pain manifestation between men and women following CAD using Mendelian randomization (MR). We used summary-level data from sex-stratified genome-wide association studies on CAD and self-reported and clinically diagnosed chest, neck and shoulder, back, and facial pain using data from the UK Biobank cohort (N > 450,000) followed by two-sample MR (sensitivity) analyses. We identified 32 and 19 independent genetic variants associated with CAD for men and women, respectively, as instrumental variables. Genetically influenced CAD was associated with a higher risk of self-reported chest pain in both men (OR: 1.27, CI: 1.2-1.33) and women (OR: 1.44, CI: 1.20-1.73), with similar results for clinically diagnosed chest pain (men OR: 1.22, CI: 1.17-1.26; women OR: 1.31, CI: 1.18-1.46). In addition, in women only, genetically influenced CAD was associated with a higher risk of back pain (OR: 1.35, CI: 1.03-1.66) and neck and shoulder pain (OR: 1.22, CI: 0.91-1.63) (p-values for interaction with men: 0.030 and 0.041, respectively). Sensitivity analysis did not indicate the results were biased by directional pleiotropy. We found evidence, based on genetic predisposition for CAD, for different pain manifestations of CAD in men and women. While CAD was associated with chest pain in both sexes, we only found evidence for a higher risk of back pain and neck and shoulder pain in women, supporting common notions that women may present more often with uncharacteristic anginal symptoms.