Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: The candidate gene association resource (CARe)

Diabetic retinopathy (DR) is the leading cause of blindness in working-age Americans1,2 and is increasing in prevalence as rates of type 2 diabetes (T2D) soar worldwide.3,4 The frequency and severity of DR are heterogeneous within and across ethnic groups,5 even with adjustment for risk factors such as duration of diabetes and glycemic control.2,6,7 There are people who have a long duration of diabetes without DR and those who have severe DR despite relatively good glycemic control. For these reasons, genetic risk factors are thought to play a role in DR. Heritability has been estimated to be as high as 27% for DR and 52% for proliferative diabetic retinopathy (PDR).8–10 However, genetic association studies for DR have been thus far limited mostly to studies of one or a modest number of candidate genes.11,12 Most reported associations have not been consistently reproduced.11,13,14 In contrast to DR, genetic association studies for T2D have revealed many consistently associated genes. Genes that increase T2D risk may also predispose to development of retinopathy. In the case of diabetic nephropathy (DN), a TCF7L2 variant increases the risk of developing DN beyond the risk of diabetes.15 Because there is evidence that DR shares risk factors and pathophysiological mechanisms with DN and macrovascular diabetic complications,6,16–21 genes associated with DN and atherosclerotic vascular disease may also be associated with DR. The Candidate gene Association Resource (CARe) is a collaboration for association analyses of genotypes and cardiovascular disease phenotypes.22 It comprises >40,000 participants from nine cohorts who have been genotyped for 49,320 single nucleotide polymorphisms (SNPs) from approximately 2,000 candidate genes postulated or known to increase risk of cardiovascular, metabolic, and inflammatory diseases.23 It includes 2691 T2D participants with fundus photographs of multiple ethnicities. Thus, the CARe framework provides an opportunity to investigate genetic associations for DR with a candidate gene approach. CARe genotyped many genes previously associated with DR,24,25 DN,25–27 and T2D.28–34 The first purpose of this study was to investigate whether these genes are also associated with the presence of DR in CARe. The second purpose was to determine whether the remaining genes included in the CARe genotyping platform, which were also chosen as potential cardiovascular disease genes, are associated with DR.