Body Mass Index and Risk of Diabetic Nephropathy: A Mendelian Randomization Study

Abstract

Context: The associations of obesity and diabetic nephropathy (DN) in type 2 diabetes are inconsistent in observational studies, and causality remains unclear.

Objective: To explore the causal effect of body mass index (BMI) on DN, estimated glomerular filtration rate (eGFR), and proteinuria in type 2 diabetes by a 2-sample Mendelian randomization (MR) analysis.

Methods: A total of 56 genetic variants were selected as instrumental variables for BMI in 158 284 participants from BioBank Japan, and their effects on DN risk, eGFR, and proteinuria were estimated in 3972 individuals with type 2 diabetes. Then, sex-stratified MR analysis was performed between BMI and DN. We selected generalized summary MR analysis as the primary method and 6 other robust methods to test MR assumptions.

Results: One SD increase in BMI was causally associated with higher DN risk [odds ratio (OR) 3.76, 95% CI 1.88-7.53, P < 0.001] and lower eGFR level (OR 0.71, 95% CI 0.59-0.86, P < 0.001). However, BMI was not causally associated with proteinuria (P = 0.22). Sex-stratified analyses indicated the causal effect of BMI on DN was stronger in women (OR 14.81, 95% CI 2.67-82.05, P = 0.002) than in men (OR 3.48, 95% CI 1.18-10.27, P = 0.02). Sensitivity analyses did not show evidence for violation of the MR assumptions.

Conclusions: Genetic evidence showed that higher BMI levels were causally associated with increased risk of DN and decreased eGFR levels. Moreover, the increase in BMI level had a greater impact on DN risk in women.

Keywords: Mendelian randomization; body mass index; diabetic nephropathy; obesity.