Association between life course adiposity and diabetic microvascular complications: A univariable and multivariable Mendelian randomization study

Our study aims to investigate the causal effects of life course adiposity on diabetic microvascular complications. Life course adiposity was considered as the exposure, including adult body mass index (BMI), childhood BMI, and birth weight, and diabetic microvascular complications were considered as the outcome, including diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DN). We utilized large-scale genome-wide association study datasets of European ancestry to conduct univariable Mendelian randomization and multivariable Mendelian randomization analyses to estimate the independent causal effects of life course adiposity on diabetic microvascular complications. Univariable Mendelian randomization analyses revealed a causal effect of high adiposity in adults and children on an increased risk of DKD, DR, and DN. Similarly, there was a causal effect of low birth weight on an increased risk of DKD and DR, but no causal relationship was found between birth weight and DN. In multivariable Mendelian randomization analyses, the causal effect of adult BMI on DN became nonsignificant, while it remained significant for both DKD and DR (DKD: inverse-variance weighted (IVW) odds ratio (OR) = 1.142, 95% confidence interval (CI) 1.029-1.829, P = .012; DR: IVW OR = 1.108, 95% CI 1.022-1.200, P = .012). Birth weight continued to demonstrate an independent causal effect on both DKD and DR (DKD: IVW OR = 0.583, 95% CI 0.430-0.790, P < .001; DR: IVW OR = 0.614, 95% CI 0.486-0.777, P < .001). Genetically predicted life course adiposity demonstrates a causal relationship with diabetic microvascular complications. Low birth weight and high adult BMI independently increase the risk of developing DKD and DR.