Do Genomic Factors Play a Role in Diabetic Retinopathy?

Abstract

Although there is strong clinical evidence that the control of blood glucose, blood pressure, and lipid level can prevent and slow down the progression of diabetic retinopathy (DR) as shown by landmark clinical trials, it has been shown that these factors only account for 10% of the risk for developing this disease. This suggests that other factors, such as genetics, may play a role in the development and progression of DR. Clinical evidence shows that some diabetics, despite the long duration of their diabetes (25 years or more) do not show any sign of DR or show minimal non-proliferative diabetic retinopathy (NPDR). Similarly, not all diabetics develop proliferative diabetic retinopathy (PDR). So far, linkage analysis, candidate gene studies, and genome-wide association studies (GWAS) have not produced any statistically significant results. We recently initiated a genomics study, the Diabetic Retinopathy Genetics (DRGen) Study, to examine the contribution of rare and common variants in the development of different phenotypes of DR, as well as their responsiveness to anti-VEGF treatment in diabetic macular edema (DME). Our preliminary findings reveal a novel set of genetic variants involved in the angiogenesis and inflammatory pathways that contribute to DR progression or protection. Further investigation of variants can help to develop novel biomarkers and lead to new therapeutic targets in DR.

Keywords: GWAS; VEGF; blood-retinal barrier; diabetic retinopathy; genetics; whole exome sequencing.

Figure 1

Schematic diagram of the experimental approach for characterizing genetic variants using next-generation sequencing (NGS).

Figure 2

Based on our clinical observations and large epidemiological studies, the hypothesis proposed is that not every diabetic retinopathy (DR) patient goes through the same sequence of events. After a period of diabetes, patients can develop mild non-proliferative diabetic retinopathy (NPDR), followed by moderate NPDR. 20% of type 2 diabetes patients develop proliferative diabetic retinopathy (PDR) while 50% of type 1 diabetes patients develop PDR. In PDR patients, only 15% develop concurrent diabetic macular edema (DME), and the other 85% never develop any macular edema. Interestingly, ~5% diabetic patients never develop DR or only have mild NPDR (1 or 2 microaneurysms, as indicated by white arrow), in spite of 20 or more years of diabetes (“Extreme Phenotype”). Images of mild NPDR and moderate NPDR phenotypes courtesy of the ETDRS Diabetic Retinopathy severity scale Ophthalmology (1991).

Figure 3

Based on a retrospective clinical study at the University of New Mexico, about 85% of proliferative diabetic retinopathy (PDR) patients do not have concurrent diabetic macular edema (DME), and, similarly, 80% of DME patients do not have concurrent PDR. There is no influence of systemic factor control in such a correlation.