RGD Reference Report - Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. - Rat Genome Database

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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.
RGD ID: 2313838
Pubmed: PMID:18458324   (View Abstract at PubMed)
PMCID: PMC2383970   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0800454105   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Diabetic Nephropathies  IAGP 2313838DNA:snp:promoter:-1125T>G(rs1617640)(human)RGD 
Diabetic Nephropathies  ISOEPO (Homo sapiens)2313838; 2313838DNA:snp:promoter:-1125T>G(rs1617640)(human)RGD 
diabetic retinopathy  IAGP 2313838DNA:snp:promoter:-1125T>G(rs1617640)(human)RGD 
diabetic retinopathy  ISOEPO (Homo sapiens)2313838; 2313838DNA:snp:promoter:-1125T>G(rs1617640)(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Epo  (erythropoietin)

Genes (Mus musculus)
Epo  (erythropoietin)

Genes (Homo sapiens)
EPO  (erythropoietin)


Additional Information