Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy.

PURPOSE: Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR. DESIGN: Case-control genetic association study. PARTICIPANTS: We evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of whom 547 (35.8%) had DR. METHODS: Participants underwent a comprehensive ocular examination, including dilated fundus photography. Retinal photographs were graded using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Odds ratios on DR. RESULTS: Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%. CONCLUSIONS: Type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors. Our findings may provide new insights to further our understanding of the genetic pathogenesis of DR.