Person: King, George
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Publication Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications
(Proceedings of the National Academy of Sciences, 2008) Tong, Z.; Yang, Z.; Patel, Shrena; Chen, 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, Jennifer; Prakash, 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, George; Bernstein, P. S.; Watkins, S.; Jorde, L. B.; Li, D. Y.; Aiello, Lloyd; Pollak, Martin; Zhang, K.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.