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Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications
- Source :
- Proceedings of the National Academy of Sciences of the United States. May 13, 2008, Vol. 105 Issue 19, p6998, 6 p.
- Publication Year :
- 2008
-
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.sup.-3]; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10-8; and Boston: P = 2.1 x [10.sup.-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. diabetic microvascular complication | end stage renal disease | proliferative diabetic retinopathy | SNP | association
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 105
- Issue :
- 19
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.179493240