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

Abstract

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.