European rational approach for the genetics of diabetic complications - EURAGEDIC: patient populations and strategy
European rational approach for the genetics of diabetic complications - EURAGEDIC: patient populations and strategy
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DOI：
10.1093/ndt/gfm501
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发表时间：
2008-01-01
影响因子：
6.1
通讯作者：
Vionnet, Nathalie
中科院分区：
文献类型：
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作者：
Tarnow, Lise;Groop, Per-Henrik;Vionnet, Nathalie
背景糖尿病肾病可能是一种复杂的遗传性状。迄今为止，大多数糖尿病肾病候选基因研究已经在小规模人群中或在匹配或表型不佳的人群中测试了有限数量的基因和变体。EURAGEDIC研究的主要目的是解决这些问题。在一项大型（n = 2499）1型糖尿病病例/对照研究中，检测候选基因的单核苷酸多态性（SNP）与显性糖尿病肾病（持续性白蛋白尿>300 mg/24 h）的相关性。在541个有或没有糖尿病肾病的独立亲子三人组中进行传递不平衡检测，以验证一致性。候选基因的选择是基于先前的连锁研究，代谢途径的知识，和动物模型。通过直接测序在100多个候选基因中进行了全面的SNP发现。总共纳入了来自三个欧洲人群（丹麦、芬兰、法国）的1176例糖尿病肾病病例和1323例长期正常白蛋白尿的糖尿病对照。收集HbA 1c、血压、尿白蛋白排泄率、肾功能、视网膜病变、吸烟、药物和心血管疾病的数据。为了总结糖尿病肾病的相关非遗传预测因子，根据EURAGEDIC数据拟合的基线表型模型包括协变量：性别、糖尿病病程、HbA（1c）和吸烟以及成对相互作用。EURAGEDIC研究旨在确定和验证作为1型糖尿病患者糖尿病肾病遗传风险因素的常见等位基因。
Background. Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems.Methods. Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n = 2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parentoffspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing.Results. In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions.Conclusions. The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients.