Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications
Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications
复制标题
DOI：
10.1073/pnas.0800454105
复制
发表时间：
2008-05-13
影响因子：
11.1
通讯作者：
Zhang, Kang
中科院分区：
文献类型：
--
作者：
Tong, Zongzhong;Yang, Zhenglin;Zhang, Kang
糖尿病患者的显著发病率和死亡率在很大程度上是由于微血管并发症的发生率大大增加。增殖性糖尿病视网膜病变(PDR)和终末期肾病(ESRD)是糖尿病最常见和最严重的微血管并发症。糖尿病患者的PDR和ESRD的发展具有高度的一致性，并且这些并发症具有很强的家族聚集性，这表明存在共同的潜在遗传机制。然而，涉及的确切基因(S)和遗传变异(S)在很大程度上仍不清楚。促红细胞生成素(EPO)是一种在糖尿病人和小鼠眼睛中观察到的强大的血管生成因子。通过病例对照关联和功能研究相结合的方法，我们证明EPO基因启动子上的SNP rs1617640的T等位基因与三个欧美队列中的PDR和ESRD显著相关[犹他州：P 1.91 x 10(-3)；糖尿病肾脏遗传学研究：P 2.66 x 10(-8)；波士顿：P=2.1 x 10(-2)]。携带TT危险基因的正常人玻璃体中EPO浓度是GG基因携带者的7.5倍。计算分析表明，rs1617640的风险等位基因(T)与EVI1/MEL1或AP1结合位点产生了矩阵匹配，导致荧光素酶报告基因的表达比G等位基因高25倍。这些结果提示EPO启动子中的rs1617640与PDR和ESRD显著相关。这项研究确定了一个疾病风险相关基因和介导严重糖尿病微血管并发症的潜在途径。
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.