Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Abstract

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P ‫؍‬ 1.91 ؋ 10 ؊3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P ‫؍‬ 2.66 ؋ 10 ؊8 ; and Boston: P ‫؍‬ 2.1 ؋ 10 ؊2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. diabetic microvascular complication ͉ end stage renal disease ͉ proliferative diabetic retinopathy ͉ SNP ͉ association

Antiangiogenic Therapy for Ischemic Retinopathies

“…This study provided the first evidence that EPO acts on the angiogenic pathway independently from VEGF and is more strongly correlated with the presence of PDR than VEGF (Watanabe et al 2005). Subsequent studies have shown genetic mutations can increase EPO expression and this is associated with increased risk of PDR and related condition in patients and in animals (Tong et al 2008;Chen et al 2009;Xiong et al 2009;Abhary et al 2010).…”

Revisiting the role of erythropoietin for treatment of ocular disorders

“…The change of genotype (TT in replacement of GG) might enhance the transcription of the EPO gene as EPO was present in higher amount in vitreous fluid, even in samples that were collected from non-diabetic individuals. 56 We have illustrated with reasonable evidence on the role, mechanism, and interaction of EPO as a therapeutic and pathological agent under different pre-clinical settings for different models of ocular disorders. These will be the basis for extrapolation to rational strategies for EPO application and administration for ocular disorders.…”

“…39,53 This study proposed that NO stimulation was regulated by the heterotrimeric interaction between EPOR/βcR/VEGF-R2 upon binding of EPO to EPOR/βcR. 39,[51][52][53][54][55] Meanwhile, studies have reported that genetic polymorphism in the EPO gene may be a pathogenic factor for acquiring risk of proliferative DR. 56 Katsura et al 55 showed that vitreous EPO was present in significantly higher amount in proliferative DR patients than in macular hole patients who had no retinopathy. The authors further showed the high EPO concentration was not induced by systemic anemia.…”

Identifying regulatory elements in eukaryotic genomes

“…However, contrary to these findings, the number of recorded cases of non-coding mutations linked to human diseases has been growing rapidly. HTRA1 promoter mutation has been linked to macular degeneration [36], PKLR promoter mutation to pyruvate kinase deficiency [37], erythropoietin promoter mutation to diabetic eye and kidney complications [38]. Multiple other promoter mutations have been also associated with different diseases [5].…”