title: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Eccles Institute of Human Genetics.
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Zhenglin
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authors.lastname: Hamam
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authors.lastname: Tonna
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authors.lastname: Constantine
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authors.initials: CC
authors.lastname: Ronquillo
authors.forename: SriniVas
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authors.lastname: Sadda
authors.forename: Robert L
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authors.lastname: Avery
authors.forename: John M
authors.initials: JM
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authors.forename: Nyall
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authors.lastname: London
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Anduze
authors.forename: George L
authors.initials: GL
authors.lastname: King
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Scott
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authors.lastname: Watkins
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Lloyd Paul
authors.initials: LP
authors.lastname: Aiello
authors.forename: Martin R
authors.initials: MR
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mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D015331:Cohort Studies; D003928:Diabetic Nephropathies / Q000150:complications* / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000150:complications* / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology
chemical_list: D012333:RNA, Messenger; D004921:Erythropoietin; D008156:Luciferases