Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications.
Authors:
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 Jorde, LB Li, DY Aiello, LP Pollak, MR Zhang, K Zhang, Kang
Citation:
Tong Z, etal., Proc Natl Acad Sci U S A. 2008 May 13;105(19):6998-7003. Epub 2008 May 5.
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.