Evaluating the associations between obesity and age-related cataract: a Mendelian randomization study

Background: The obesity-cataract association has been inconsistently reported. The fat mass and obesity-related (FTO) singlenucleotide polymorphism (SNP) rs9939609 is a major SNP associated with obesity and has been used as an instrumental variable for obesity in aMendelian randomization (MR) approach. An interaction between the FTO SNP and macronutrient intake for obesity was suggested previously. Objective: The aim of this study was to assess the associations between obesity and cataract, using FTO SNP rs9939609 as an instrumental variable in an MR approach, and explore interactions of this SNP with macronutrient intake in relation to risk of cataract in a population-based cohort. Methods: The Blue Mountains Eye Study (BMES) is a longitudinal population-based study of common eye disease. Of 3654 baseline participants of the BMES (1992-1994), 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were followed 5 and 10 y later. During the 5-y follow-up, 1174 new participants were examined. Cumulative cataract was defined as the presence of cortical, nuclear, or posterior subcapsular (PSC) cataract at any visit, following the Wisconsin Cataract Grading System. Imputed dosage of the FTO SNP rs9939609 was used. Quintiles of macronutrient intake (carbohydrates, protein, fats) were derived from an FFQ. ORs and 95% CIs were estimated using multivariable-adjusted logistic regression models. Results: After multivariable adjustment, there were no associations between BMI and any cataract types in MR models using rs9939609 as an instrumental variable. However, an interaction between rs9939609 and protein intake for PSC cataract risk was suggested (P = 0.03). In analyses stratified by quintiles of protein intake, each minor allele of rs9939609 was associated with increased odds of PSC (OR: 2.14; 95% CI: 1.27, 3.60) in the lowest quintile subgroup only. Conclusions: Obesity was not causally associated with age-related cataract. However, among persons in the lowest quintile of protein intake, obesity may be associated with PSC cataract.