title: Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy.
abstract: 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.
  
  
  
  Case-control genetic association study.
  
  
  
  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.
  
  
  
  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).
  
  
  
  Odds ratios on DR.
  
  
  
  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%.
  
  
  
  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.
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Duke-NUS Medical School, Singapore.
authors.forename: Yong He
authors.initials: YH
authors.lastname: Chong
authors.affiliation: Duke-NUS Medical School, Singapore.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
authors.forename: Yih Chung
authors.initials: YC
authors.lastname: Tham
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
authors.forename: Alfred
authors.initials: A
authors.lastname: Gan
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
authors.forename: Shu Pei
authors.initials: SP
authors.lastname: Tan
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
authors.forename: Gavin
authors.initials: G
authors.lastname: Tan
authors.affiliation: Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Duke-NUS Medical School, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Tien Yin
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Duke-NUS Medical School, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: chingyu.cheng@duke-nus.edu.sg.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Cheng
mesh_terms: D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012846:Singapore / Q000453:epidemiology