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Publication Information
Affiliation
Department of Ophthalmology and Visual Sciences, Eccles Institute of Human Genetics.
Authors
Aiello LP, Anduze AL, Avery RL, Banerjee N, Bernstein PS, Brand JM, Buehler J, Cameron DJ, Chen H, Chen Y, Constantine R, Genetics of Diabetes and Diabetic Complication Study Group, Gibbs D, Goldfarb-Rumyantzev A, Hamam RN, Harmon J, Hau VS, Jorde LB, Kaminoh Y, Katz BJ, Keenan H, King GL, Li DY, London N, Luo L, Mamalis N, Ma X, Patel S, Pearson E, Perez C, Pollak MR, Prakash M, Rabena M, Ronquillo CC, Sadda S, Sun JK, Tinkham NH, Tong Z, Tonna S, Watkins S, Yang X, Yang Z, Yu B, Zabriskie NA, Zeng J, Zhang K
Studies
Citation
Tong Z, Yang Z, Patel S, Chen H, Gibbs D, Yang X, Hau VS, Kaminoh Y, Harmon J, Pearson E, Buehler J, Chen Y, Yu B, Tinkham NH, Zabriskie NA, Zeng J, Luo L, Sun JK, Prakash M, Hamam RN, Tonna S, Constantine R, Ronquillo CC, Sadda S, Avery RL, Brand JM, London N, Anduze AL, King GL, Bernstein PS, Watkins S, Genetics of Diabetes and Diabetic Complication Study Group, Jorde LB, Li DY, Aiello LP, Pollak MR, Zhang K. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A 2008 May 13;105(19):6998-7003. Epub 2008 May 5.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 x 10(-3); Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10(-8); and Boston: P = 2.1 x 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.