Causal Associations of Obesity with Chronic Kidney Disease and Arterial Stiffness: A Mendelian Randomization Study

Abstract

Context: Observational studies have been associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. Objective: We aimed to investigate the causality of obesity with CKD and arterial stiffness using mendelian randomization (MR) analysis. Methods: We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11 384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single-nucleotide variations (SNVs, formerly single-nucleotide polymorphisms [SNPs]) were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2. Arterial stiffness was defined as brachial-ankle pulse wave velocity greater than 1550 cm/s. Results: Using the genetic risk score as the IV, we demonstrated causal relations of each 1-SD increment in BMI with CKD (odds ratio [OR]: 2.36; 95% CI, 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI, 1.22-2.39). Using the 14 SNVs individually as IVs, each 1-SD increment in BMI was casually associated with CKD (OR: 2.58; 95% CI, 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI, 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (both P for intercept ≥ .34). The causality between obesity and CKD was validated in 2-sample MR analysis among Europeans (681 275 of Genetic Investigation of ANthropometric Traits and 133 413 of CKD Genetics). Conclusion: This study provided novel insights into the causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.