Assessing the Effects of Childhood and Adult Body Mass Index on Diabetic Retinopathy Risk: A Mendelian Randomization Study.

OBJECTIVE: Obesity is linked to Diabetic Retinopathy (DR), but the relationship between childhood obesity and DR remains unclear. This study uses Mendelian Randomization (MR) to investigate this link. METHODS: Univariate MR assessed the associations between childhood and adult Body Mass Index (BMI) and DR risk, followed by multivariable MR to distinguish their specific effects. Summary data were obtained from the Early Growth Genetics Consortium (childhood BMI), GIANT (adult BMI), and FinnGen (DR). Sensitivity analyses ensured robustness. RESULTS: Genetically predicted childhood BMI was positively associated with DR (OR, 1.20; 95% CI, 1.07-1.34), background DR (BDR: OR, 1.44; 95% CI, 1.16-1.79), and proliferative DR (PDR: OR, 1.22; 95% CI, 1.08-1.39). Adult BMI also increased odds (DR: OR, 1.40; 95% CI, 1.28-1.52; BDR: OR, 1.50; 95% CI, 1.21-1.86; PDR: OR, 1.41; 95% CI, 1.26-1.57). After adjusting for adult BMI, the effect of childhood BMI was reduced, whereas the effect of adult BMI remained statistically significant. Sensitivity analyses confirmed robustness. DISCUSSION: The positive association between childhood BMI and DR is mediated through adult BMI, while adult BMI exerts an independent direct effect. This highlights distinct roles of obesity at different life stages and underscores life-course weight management. Potential drug targets (e.g., Glucagon-like peptide-1 receptor agonists and anti-VEGF agents) may offer therapeutic avenues. CONCLUSION: Genetically predicted childhood BMI is positively associated with DR risk, an effect mediated by adult BMI. Maintaining a healthy weight from childhood through adulthood is therefore crucial for DR prevention. Targeting obesity-related pathways warrants further investigation.