Environmental factors, serum biomarkers and risk of atrial fibrillation: an exposure-wide umbrella review of meta-analyses

Atrial fibrillation (AF) is the most common cardiac arrhythmia. We designed an umbrella review to systematically assess the epidemiological credibility of the associations of non-genetic factors with risk of AF. We searched PubMed and EMBASE from inception to December 31, 2018 to identify systematic reviews and meta-analyses of observational studies for the association of non-genetic factors with risk of AF. For each meta-analysis, we used the random-effects model, and we estimated the 95% confidence and prediction intervals. We also assessed between-study heterogeneity, small-study effects and excess significance bias. We identified 34 eligible papers that examined 51 associations of 42 unique non-genetic factors with risk of AF. Eighteen associations remained statistically significant at P value < 1 × 10⁻⁶. Thirty-one associations presented large or very large between-study heterogeneity. Eight associations presented evidence for small-study effects and 13 associations had evidence for excess significance bias. Ten associations, i.e. corrected QT interval, alcohol consumption (highest vs. lowest category, per 1 drink/day increase), body mass index (> 30 units vs. < 30 units, per 5 units increase), waist circumference, body weight, type 2 diabetes mellitus, and smoking (ever vs. never, per 10 cigarettes/day increase) were supported by convincing or highly suggestive evidence in meta-analyses of prospective cohort studies. Type 2 diabetes mellitus, markers of adiposity, alcohol consumption, smoking, and corrected QT interval constitute credible risk factors of AF. Our proposed grading may guide the design of future studies, including Mendelian randomization studies, to assess whether these associations are causal.