Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications by Tong Zongzhong, Yang Zhenglin, Patel Shrena, Chen Haoyu, Gibbs Daniel, Yang Xian, Hau Vincent S, Kaminoh Yuuki, Harmon Jennifer, Pearson Erik, Buehler Jeanette, Chen Yuhong, Yu Baifeng, Tinkham Nicholas H, Zabriskie Norman A, Zeng Jiexi, Luo Ling, Sun Jennifer K, Prakash Manvi, Hamam Rola N, Tonna Stephen, Constantine Ryan, Ronquillo Cecinio C, Sadda SriniVas, Avery Robert L, Brand John M, London Nyall, Anduze Alfred L, King George L, Bernstein Paul S, Watkins Scott, Genetics of Diabetes and Diabetic Complication Study Group, Jorde Lynn B, Li Dean Y, Aiello Lloyd Paul, Pollak Martin R, Zhang Kang in Proceedings of the National Academy of Sciences of the United States of America (2008).

[PMID: 18458324] PubMed


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.

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