NDT Advance Access published online on August 17, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm501
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European rational approach for the genetics of diabetic complications—EURAGEDIC: patient populations and strategy
1Steno Diabetes Center, Copenhagen, Denmark, 2Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, 3Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Finland, 4CHU Poitiers, University Hospital, Endocrinology, Poitiers, 5INSERM, ERM 324, Poitiers, France, 6Welcome Trust Centre for Human Genetics, Oxford, UK, 7INSERM, UMR S 525, 8Université Pierre et Marie Curie-Paris 6, UMR S 525, F-75634, 9Department of Diabetology, Bichat Hospital 10INSERM, U695, Xavier Bichat University of Medicine, Paris, 11CNG, Evry, France, 12Mammalian Research Council, Oxford, UK and 13Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark
Correspondence and offprint requests to: Lise Tarnow, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Email: ltar{at}steno.dk
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Abstract |
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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 parent–offspring 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 HbA1c, 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, HbA1c 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.
Keywords: diabetic nephropathy; genetics; type 1 diabetes
Received for publication: 30. 1.07
Accepted in revised form: 3. 7.07
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