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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
19
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pubmed:dateCreated |
2008-5-14
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1091-6490
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pubmed:author |
pubmed-author:AielloLloyd PaulLP,
pubmed-author:AnduzeAlfred LAL,
pubmed-author:AveryRobert LRL,
pubmed-author:BernsteinPaul SPS,
pubmed-author:BrandJohn MJM,
pubmed-author:BuehlerJeanetteJ,
pubmed-author:ChenHaoyuH,
pubmed-author:ChenYuhongY,
pubmed-author:ConstantineRyanR,
pubmed-author:Genetics of Diabetes and Diabetic Complication Study Group,
pubmed-author:GibbsDanielD,
pubmed-author:HamamRola NRN,
pubmed-author:HarmonJenniferJ,
pubmed-author:HauVincent SVS,
pubmed-author:JordeLynn BLB,
pubmed-author:KaminohYuukiY,
pubmed-author:KingGeorge LGL,
pubmed-author:LevyJ BJB,
pubmed-author:LiDean YDY,
pubmed-author:LondonNyallN,
pubmed-author:PatelShrenaS,
pubmed-author:PearsonErikE,
pubmed-author:PollakMartin RMR,
pubmed-author:PrakashManviM,
pubmed-author:RonquilloCecinio CCC,
pubmed-author:SaddaSriniVasS,
pubmed-author:SunJennifer KJK,
pubmed-author:TinkhamNicholas HNH,
pubmed-author:TongZongzhongZ,
pubmed-author:TonnaStephenS,
pubmed-author:WatkinsScottS,
pubmed-author:XianYangY,
pubmed-author:YangZhenglinZ,
pubmed-author:YuBaifengB,
pubmed-author:ZabriskieNorman ANA,
pubmed-author:ZengJiexiJ,
pubmed-author:ZhangKangK
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
105
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pubmed:owner |
NLM
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