Disentangling the association between kidney function and atrial fibrillation:a bidirectional Mendelian randomization study

Background: The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis. From multiple genome-wide association studies (GWAS), we retrieved genetic variants associated with kidney function (estimated glomerular filtration rate based on creatinine (eGFRcreat), blood urea nitrogen (BUN), chronic kidney disease (CKD stage ≥G3): n = 1,045,620, eGFR based on cystatin C: n = 24,063-32,861, urine albumin-tocreatinine ratio (UACR), and microalbuminuria: n = 564,257), and AF (n = 1,030,836). The inverse-variance weighted method was used as our main analysis. Results: MR analyses supported a causal effect of CKD (n = 9 SNPs, odds ratio (OR): 1.10, 95% confidence interval (CI): 1.04–1.17, p-value = 1.97 × 10− 03), and microalbuminuria (n = 5 SNPs, OR: 1.26, 95% CI: 1.10–1.46, pvalue = 1.38 × 10− 03) on AF risk. We also observed a causal effect of AF on eGFRcreat (n = 97 SNPs, OR: 1.00, 95% CI: 1.00–1.00, p-value = 6.78 × 10− 03), CKD (n = 107 SNPs, OR: 1.06, 95% CI: 1.03–1.09, p-value = 2.97 × 10− 04), microalbuminuria (n = 83 SNPs, OR: 1.07, 95% CI: 1.04–1.09, p-value = 2.49 × 10− 08), and a suggestive causal effect on eGFRcys (n = 103 SNPs, OR: 0.99, 95% CI: 0.99–1.00, p-value = 4.61 × 10− 02). Sensitivity analyses, including weighted median estimator, MR-Egger, the MR pleiotropy residual sum and outlier test, and excluding genetic variants associated with possible confounders and/or horizontal mediators (myocardial infarction/coronary artery disease, heart failure) indicated that these findings were robust. Conclusions: Our results supported a bidirectional causal association between kidney function and AF. The shared genetic architecture between kidney dysfunction and AF might represent potential important therapeutic targets to prevent both conditi