Assessment of the causal association between celiac disease and cardiovascular diseases

BACKGROUND: Epidemiological studies have reported inconsistent results of the association between celiac disease (CD) and cardiovascular diseases. Moreover, the causality remains largely unknown. Therefore, we aimed to investigate whether CD is causally associated cardiovascular diseases, including ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, coronary heart disease, myocardial infarction, angina, heart failure, atrial fibrillation, and venous thromboembolism using an mendelian randomization (MR) approach. METHODS: Summary-level data for CD were derived from a large-sample genome-wide association study (GWAS) including 12,041 CD cases and 12,228 controls of European ancestry. The corresponding data for ischemic stroke (34,217 cases and 406,111 controls), large artery stroke (4,373 cases and 406,111 controls), cardioembolic stroke (7,193 cases and 406,111 controls), small vessel stroke (5,386 cases and 192,662 controls), coronary heart disease (22,233 cases and 64,762 controls), myocardial infarction (11,622 cases and 187,840 controls), angina (18,168 cases and 187,840 controls), heart failure (47,309 cases and 930,014 controls), atrial fibrillation (60,620 cases and 970,216 controls), and venous thromboembolism (9,176 cases and 209,616 controls) were obtained from the IEU GWAS database. We calculated the causal effect using the inverse variance weighted method. Sensitivity analyses and leave-one-out analyses were performed to ensure the consistency and robustness of causal estimates. RESULTS: The MR inverse variance weighted estimates indicated no causal effect of genetically predicted CD on ischemic stroke (OR = 1.001, 95% CI: 0.984-1.018), large artery stroke (OR = 1.003, 95% CI: 0.961-1.048), cardioembolic stroke (OR = 1.009, 95% CI: 0.977-1.042), small vessel stroke (OR = 1.023, 95% CI: 0.981-1.066), coronary heart disease (OR = 0.995, 95% CI: 0.977-1.013), myocardial infarction (OR = 0.994, 95% CI: 0.959-1.030), angina (OR = 1.006, 95% CI: 0.981-1.032), heart failure (OR = 0.999, 95% CI: 0.982-1.016), atrial fibrillation (OR = 1.000, 95% CI: 0.990-1.011), and venous thromboembolism (OR = 1.001, 95% CI: 0.971-1.032). Sensitivity analyses using the MR-Egger, weighted median, and simple mode methods yielded similar results. No evidence of horizontal pleiotropy was identified (MR Pleiotropy Residual Sum and Outlier global test and MR-Egger intercept with P > 0.05). CONCLUSION: Our findings do not support a causal contribution of CD itself to ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, coronary heart disease, myocardial infarction, angina, heart failure, atrial fibrillation, and venous thromboembolism risk.