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Rainald G. Schmidt-Kastner, Magda R. AbdelFattah; Expression of Diabetes Risk Genes in the Retina Explored in Silico. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5932.
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Candidate and genome-wide association studies have identified genes associated with the risk of diabetes mellitus (type 2) that are related to pancreatic beta-cell dysfunction. Long-standing hyperglycemia then causes diabetic retinopathy through vascular mechanisms. Experimental and clinical research has identified an impairment of retinal ganglion cells in diabetes that may be independent of vascular factors. Based on our previous work on WFS1/wolframin in retinal neurons (Exp. Eye Res. 89: 568, 2009), it was hypothesized that diabetes risk genes expressed in the retina may directly affect metabolism of retinal neurons. Consequently, expression of diabetes risk genes in the retina was explored in silico using public databases.
Diabetes risk genes (n=133) were compiled from the literature, reviews and HuGE database. Monogenic disorders with diabetes were included (OMIM). Expression in the retina was explored through EYESAGE (NEIBank) by using the number of hits for WFS1 as reference. Neuronal expression was estimated by using mRNA hybridization maps of the mouse brain (Allen Brain Atlas-ABA).
Retinal expression signals were found for n=27 (20%) of diabetes risk genes using EYESAGE. In addition to WFS1, neuronal expression was found for n=18 of these in the ABA, i.e. ADAMTS9, BSCL2, EIF2AK3, EXT2, FABP2, FTO, FXN, GRB10, IRS1, IRS2, LMNA, NEUROD1, NRF1, PAX6, PCSK1, PIK3R1, RAPGEF1, and TSPAN8. Seven of these genes entered the analysis through a monogenic disorder with diabetes.
The present in silico analysis indicates that several diabetes risk genes are expressed in the retina which may be in retinal neurons. It remains to be studied whether the same splice variants are expressed in retina and pancreatic beta-cells. Functional studies of the retina expressing variants of diabetes risk genes may clarify whether intrinsic neuronal mechanisms contribute to diabetic retinopathy. SNPs in WFS1 reproducibly associated with the risk of type 2 diabetes could be a starting point for such an analysis, because pathogenic mutations of WFS1 cause retinal degeneration and optic atrophy.
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