Heritability of the Severity of Diabetic Retinopathy: The FIND-Eye Study

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are serious microvascular complications of type 1 and 2 diabetes mellitus (DM).1 DR is a leading cause of blindness among adults in the United States, affecting more than 60% of individuals with type 2 DM.2 Approximately 4.1 million American adults have DR, and one of every 12 diabetic persons older than 40 years has vision-threatening retinopathy.3 The development and progression of DR is associated with the duration of diabetes in both type 1 and 2 diabetic patients.4 Nearly all patients with type 1 diabetes and 60% of patients with type 2 diabetes have retinopathy during the first two decades of disease. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), 3.6% of younger-onset patients (type 1 diabetes) and 1.6% of older-onset patients (type 2 diabetes) were legally blind. In the younger-onset group, 86% of blindness was attributable to DR. In the older-onset group, in which other eye diseases were common, one-third of the cases of legal blindness were due to DR.4,5 DR is characterized by microvascular abnormalities, proliferation of retinal vessels and increased retinal vascular permeability, leading to the development of nonproliferative DR (NPDR), proliferative DR (PDR), and macular edema (DME), respectively.6 Vision loss in DR can result from several mechanisms. Central vision may be impaired by macular edema or capillary nonperfusion. New blood vessels of PDR and contraction of the accompanying fibrous tissue can distort the retina and lead to tractional retinal detachment, producing severe and often irreversible vision loss. In addition, the new blood vessels may bleed, adding further complications of preretinal or vitreous hemorrhage.4 Currently, the gold standard for determining severity of DR is the grading system that has been modified and tested by the Early Treatment Diabetic Retinopathy Study (ETDRS), on seven standard field 35-mm stereoscopic color fundus photographs.7 This system takes into consideration the severity of the abnormalities characterizing both nonproliferative and proliferative retinopathy, including neovascularization, fibrous proliferation, vitreous and preretinal hemorrhage, and scars of panretinal photocoagulation. The presence of DR, as well as the type of retinal lesions, aggregates in families.8–10 It has been suggested that Hispanic individuals with diabetes develop severe retinopathy earlier in their course and progress more rapidly compared with African Americans or European Americans.11,12 These observations were independent of glycemic control and measured environmental factors. A lower prevalence of DR has also been reported in diabetic African Americans compared with that in European Americans.9 In the families in the Diabetes Control and Complications Trial (DCCT), the risk of severe DR was higher among relatives of subjects with severe DR than in relatives of those with mild or moderate DR.13 In South-Indian families containing multiple type 2 diabetic siblings, the prevalence of DR was three times higher in siblings of probands with DR than in those without.14 DN is a microvascular complication of diabetes that is characterized by persistent albuminuria and secondarily elevated blood pressure, followed by a progressive decline in kidney function. It is the most common cause of end-stage renal disease (ESRD) worldwide and accounts for 40% of incident dialysis patients in the United States.15 DN clusters in families with both type 1 and 2 diabetes, suggesting a genetic component to the development and/or progression of disease.16–21 DR and DN frequently coexist; DR is more severe in patients with severe DN and those with advanced DN have far more severe lesions of DR than do those without DN.1,8 The rate of renal disease progression among proteinuric patients with type 2 DM is reportedly faster in those with concomitant retinopathy, after adjustment for blood pressure, metabolic, and lipid control.22 Relatively few existing data sets have included factors influencing correlations between DR and DN in multiplex diabetic families or across different ethnic groups. The FIND study was initiated to map genes influencing DN susceptibility. FIND enrolled families with probands who had advanced DN, along with their diabetic siblings, concordant and discordant for nephropathy. All FIND family study members were invited to participate in the FIND-Eye substudy in an attempt to localize genes underlying susceptibility to DR. Our goal was to assess the following hypotheses: (1) Is the severity of DR associated with the presence and severity of nephropathy in individuals with diabetes mellitus, and (2) is the severity of DR under significant familial influence in members of multiplex diabetic families?