Abstract
BackgroundThe potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear. MethodsWe 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-to-creatinine ratio (UACR), and microalbuminuria: n = 564,257), and AF (n = 1,030,836). The inverse-variance weighted method was used as our main analysis. ResultsMR 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, p-value = 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. ConclusionsOur 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 conditions in the general population.
Highlights
Chronic kidney disease (CKD) and atrial fibrillation (AF) are both common conditions which carry independent risks for cardiovascular morbidity and mortality [1–7]
From multiple genome-wide association studies (GWAS), we retrieved genetic variants associated with kidney function (esti mated glomerular filtration rate based on creatinine, blood urea nitrogen (BUN), chronic kidney disease (CKD stage ≥G3): n = 1,045,620, estimated glomerular filtration rate (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)
Within the European study sample, a total of 256 genome-wide sig nificant index genetic variants were associated with eGFRcreat of which 19 were genome-wide significantly associated with CKD stage ≥G3
Summary
Chronic kidney disease (CKD) and atrial fibrillation (AF) are both common conditions which carry independent risks for cardiovascular morbidity and mortality [1–7]. On the one hand, reduced kidney function may lead to AF through increased activity of the renin-angiotensin-aldosterone system (RAAS) [9–16], hypertension [9,16], left ventricular hypertrophy [9], inflam mation [9,17–19] and by promoting cardiovascular diseases such as coronary heart disease, and heart failure [5,9,20]. AF may give rise to kidney dysfunction through activation of RAAS [9], hypoperfusion [9], thromboembolism [9], inflammation [9], and by inducing other cardiovascular diseases [5,9,20]. This complex interplay between the kidneys and the heart may result in a vicious cycle in which each condition promotes initiation and progression of the other condi tion [5,9,20]. The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear. The shared genetic architecture between kidney dysfunction and AF might represent potential important therapeutic targets to prevent both conditions in the general population
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