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Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications.


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.

SUBMITTER: Tong Z 

PROVIDER: S-EPMC2383970 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications.

Tong Zongzhong Z   Yang Zhenglin Z   Patel Shrena S   Chen Haoyu H   Gibbs Daniel D   Yang Xian X   Hau Vincent S VS   Kaminoh Yuuki Y   Harmon Jennifer J   Pearson Erik E   Buehler Jeanette J   Chen Yuhong Y   Yu Baifeng B   Tinkham Nicholas H NH   Zabriskie Norman A NA   Zeng Jiexi J   Luo Ling L   Sun Jennifer K JK   Prakash Manvi M   Hamam Rola N RN   Tonna Stephen S   Constantine Ryan R   Ronquillo Cecinio C CC   Sadda SriniVas S   Avery Robert L RL   Brand John M JM   London Nyall N   Anduze Alfred L AL   King George L GL   Bernstein Paul S PS   Watkins Scott S   Jorde Lynn B LB   Li Dean Y DY   Aiello Lloyd Paul LP   Pollak Martin R MR   Zhang Kang K  

Proceedings of the National Academy of Sciences of the United States of America 20080505 19


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 mech  ...[more]

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