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The Role of Genetics in Susceptibility to Diabetic Retinopathy

Diabetic retinopathy remains the leading cause of blindness in working-aged adults.(1) Over 4 million adults 40 years and older in the United States are estimated to have diabetic retinopathy, of whom 1 out of every 12 has advanced vision-threatening retinopathy (2). With the projected increase in the world-wide prevalence of diabetes to 380 million people by 2025,(3;4) of whom 40% are expected to have some form of diabetic retinopathy,(2) there is a clearly a need to develop strategies to identify persons at risk of diabetic retinopathy, allowing prevention and early intervention. 
 
Risk Factors for Diabetic Retinopathy 
There is already strong evidence that longer duration of diabetes, poorer control of blood glucose and elevated blood pressure are the major factors responsible for the onset and progression of diabetic retinopathy. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a population-based cohort study of diabetes in which participants were first examined in 1980-82, showed that in persons with type 1 diabetes, the prevalence of diabetic retinopathy ranged from 17% in those with diabetes for less than 5 years to almost 100% in those with diabetes for over 15 years.(5) The corresponding figures in persons with type 2 diabetes were 29% and 78%.(6) The importance of good glycemic control for delaying the development and progression of diabetic retinopathy was confirmed in two landmark clinical trials, the Diabetes Control and Complications Trial (DCCT) in persons with type 1 diabetes,(7) and the UK Prospective Diabetes Study (UKPDS) in persons with type 2 diabetes.(8) The UKPDS has further shown the value of tight blood pressure control in delaying the development of diabetic retinopathy complications and well as other microvascular endpoints.(9;10) More recently, the Fenofibrate Intervention and Event Lowering in Diabetes Study(11) indicated that lipid lowering therapy might reduce retinopathy requiring laser treatment. 
 
Nonetheless, diabetic retinopathy occurs even with optimal glucose and blood pressure control. The newly completed ADVANCE trial recruited 11,140 patients with type 2 diabetes and found intensive glucose control to reduce glycosylated hemoglobin to 6.5% or lower had no effect on the 5-year incidence of retinopathy rates. ADVANCE also reported that lowering of blood pressure to near normal levels (approximately 140/80) did not achieve further reduction in progression of diabetic retinopathy.(12) In addition, it is clinically apparent that some patients with poor control of glycemia or blood pressure do not develop diabetic retinopathy even over prolonged periods of time, while others may develop diabetic retinopathy in relatively short periods of time despite good risk factor control. This was prominently illustrated in the Joslin Medalist study which found that almost 50% of older diabetic participants in their study had no evidence of retinopathy despite surviving over 50 years with type 1 diabetes.(13) Finally, a recent observational study of 11,423 participants from three diverse populations,(14) reported that retinopathy signs, mainly retinal microaneurysms, characteristic of diabetes were detectable in 7.4-13.4% of nondiabetic participants, and were present even in individuals with glycosylated hemoglobin levels <5.0%. These results suggest that processes other than hyperglycemia and elevated blood pressure contribute to the development and progression of diabetic retinopathy.