Tong, Z.Yang, Z.Patel, ShrenaChen, H.Gibbs, D.Yang, X.Hau, V. S.Kaminoh, Y.Harmon, J.Pearson, E.Buehler, J.Chen, Y.Yu, B.Tinkham, N. H.Zabriskie, N. A.Zeng, J.Luo, L.Sun, JenniferPrakash, M.Hamam, R. N.Tonna, S.Constantine, R.Ronquillo, C. C.Sadda, S.Avery, R. L.Brand, J. M.London, N.Anduze, A. L.King, GeorgeBernstein, P. S.Watkins, S.Jorde, L. B.Li, D. Y.Aiello, LloydPollak, MartinZhang, K.2016-10-252008Tong, Z., Z. Yang, S. Patel, H. Chen, D. Gibbs, X. Yang, V. S. Hau, et al. 2008. Promoter Polymorphism of the Erythropoietin Gene in Severe Diabetic Eye and Kidney Complications. Proceedings of the National Academy of Sciences 105, no. 19: 6998–7003. doi:10.1073/pnas.0800454105.0027-8424http://nrs.harvard.edu/urn-3:HUL.InstRepos:29074747Significant 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.en-USdiabetic microvascular complicationend stage renal diseaseproliferative diabetic retinopathySNPassociationJournal Article2016-10-2510.1073/pnas.0800454105