Microvascular Complications Of Diabetes, Susceptibility To, 2

A number sign (#) is used with this entry because of evidence that susceptibility to microvascular complications of diabetes-2 is associated with variation in the gene encoding erythropoietin (EPO; 133170) on chromosome 7q21.

For a discussion of genetic heterogeneity of susceptibility to microvascular complications of diabetes, see MVCD1 (603933).

Pathogenesis

Although vascular endothelial growth factor (VEGF; 192240) is a primary mediator of retinal angiogenesis, VEGF inhibition alone is insufficient to prevent retinal neovascularization. Hence, it was postulated that there are other potent ischemia-induced angiogenic factors, such as erythropoietin. Watanabe et al. (2005) found that the median vitreous EPO level in 73 patients with proliferative diabetic retinopathy was significantly higher than that in 71 patients without diabetes. The median VEGF level in patients with retinopathy was also significantly higher than that in patients without diabetes. Multivariate logistic-regression analyses indicated that EPO and VEGF were independently associated with proliferative diabetic retinopathy and that EPO was more strongly associated with the presence of proliferative diabetic retinopathy than was VEGF. The authors concluded that EPO is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy. They suggested that EPO blockade might be beneficial in the treatment of proliferative diabetic retinopathy, but cautioned that EPO blockade may be hazardous for retinal diseases that involve apoptosis of retinal photoreceptors since EPO is a survival factor for retinal photoreceptors and acts as a neurologic protection factor in diabetic neuropathy.

Molecular Genetics

Tong et al. (2008) genotyped 19 SNPs in 11 genes involved in angiogenesis in 374 patients with type 2 diabetes (125853) and both proliferative diabetic retinopathy (PDR) and end-stage renal disease (ESRD) and 239 age- and ethnicity-matched diabetic controls; the only significant association (corrected p = 0.036) was at rs1617640 in the promoter of the EPO gene (133170.0001). To investigate whether rs1617640 was specifically associated with diabetic microvascular complications rather than with complications of type 2 diabetes per se, the authors replicated the study in 365 patients with type 1 diabetes (222100) with both PDR and ESRD, 500 with nephropathy and retinopathy without progression to PDR and ESRD, and 574 type 1 diabetic control patients without nephropathy or retinopathy, and found that the T allele of rs1617640 was significantly associated (p = 2.66 x 10(-8)) with PDR and ESRD; the results were confirmed in a third cohort involving 379 type 1 diabetics with both PDR and nephropathy and 141 diabetic controls (p = 0.021). The EPO concentration in vitreous samples was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype, and studies in cultured HEK293 cells showed that the T allele enhanced luciferase reporter expression by 25-fold compared with that of the G allele (p = 4.7 x 10(-29)).