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

Abstract

Abstract Background Observational studies suggest that kidney function and atrial fibrillation (AF) are bidirectionally associated. Whether this bidirectional association is causal remains unclear. Purpose To investigate the causality of the bidirectional association between kidney function and AF. Methods Genetic variants associated with different measures of kidney function including estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcreat), blood urea nitrogen (BUN), chronic kidney disease (CKD, eGFR <60ml/min/1.73m2), eGFR based on cystatin (eGFRcys), urine albumin-to-creatinine ratio (UACR) and microalbuminuria (MA, UACR >30mg/g) were retrieved from multiple Genome-Wide Association Studies (GWAS). These GWAS were all part of the Chronic Kidney Disease Genetics (CKDGen) Consortium (n=24,063–1,040,070). Genetic variants associated with AF were retrieved from a GWAS on AF (n=1,030,836). We used two-sample MR analyses to assess the potential causality of the bidirectional association between kidney function and AF. Results MR analyses supported a causal effect of genetically predicted BUN, CKD and MA on AF risk (for BUN: n=18 SNPs, outlier corrected odds ratio (OR): 2.05, per 1 unit increase of BUN (mg/dL), 95% CI: 1.30–3.25, p-value = 2.13E-03. For CKD: n=9 SNPs, outlier corrected OR: 1.10, 95% CI: 1.04–1.17, p-value = 1.97E-03. For MA: n=5 SNPs, outlier corrected OR: 1.26, 95% CI: 1.10–1.46, p-value = 1.38E-03). MR analyses also supported a causal effect of genetically predicted AF on eGFRcreat (n=97 SNPs, outlier corrected OR: 0.998, per 1 unit increase of log transformed eGFRcreat (ml/min/1.73m2), 95% CI: 0.997–0.999, p-value = 6.78E-03), CKD risk (n=107 SNPs, outlier corrected OR: 1.06, 95% CI: 1.03–1.09, p-value = 2.97E-04) and MA risk (n=83 SNPs, outlier corrected OR: 1.07, 95% CI: 1.04–1.09, p-value = 2.49E-08). A suggestive causal effect of genetically predicted AF on eGFRcys was found (n=103 SNPs, outlier corrected OR: 0.993, per 1 unit increase of log transformed eGFRcys (ml/min/1.73m2), 95% CI: 0.986–0.999, p-value = 4.60E-02). MR analyses did not support a significant causal effect of the other kidney function measures on AF risk and vice versa. Moreover, sensitivity analyses, including weighted median estimator (WME), MR-Egger and the MR pleiotropy residual sum and outlier test (MR-PRESSO) indicated that these findings were robust. Furthermore, the associations did not change when genetic variants associated with coronary artery disease and heart failure were excluded. Conclusions MR analyses supported a bidirectional causal association between kidney function and AF. Our findings carry the potential for identification of important therapeutic targets for both conditions with implications for secondary prevention. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Erasmus Medical Center and Erasmus University, Rotterdam Forest plot with the MR effect estimatesBidirectional MR: Kidney function and AF