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Assessment of 115 Candidate Genes for Diabetic Nephropathy by Transmission/Disequilibrium Test

¹ Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
² Department of Medicine, Center for Diabetic Kidney Disease, Division of Nephrology, Thomas Jefferson University, Philadelphia, Pennsylvania
³ Renal-Electrolyte and Hypertension Division and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Several lines of evidence, including familial aggregation, suggest that allelic variation contributes to risk of diabetic nephropathy. To assess the evidence for specific susceptibility genes, we used the transmission/disequilibrium test (TDT) to analyze 115 candidate genes for linkage and association with diabetic nephropathy. A comprehensive survey of this sort has not been undertaken before. Single nucleotide polymorphisms and simple tandem repeat polymorphisms located within 10 kb of the candidate genes were genotyped in a total of 72 type 1 diabetic families of European descent. All families had at least one offspring with diabetes and end-stage renal disease or proteinuria. As a consequence of the large number of statistical tests and modest P values, findings for some genes may be false-positives. Furthermore, the small sample size resulted in limited power, so the effects of some tested genes may not be detectable, even if they contribute to susceptibility. Nevertheless, nominally significant TDT results (P < 0.05) were obtained with polymorphisms in 20 genes, including 12 that have not been studied previously: aquaporin 1; B-cell leukemia/lymphoma 2 (bcl-2) proto-oncogene; catalase; glutathione peroxidase 1; IGF1; laminin alpha 4; laminin, gamma 1; SMAD, mothers against DPP homolog 3; transforming growth factor, beta receptor II; transforming growth factor, beta receptor III; tissue inhibitor of metalloproteinase 3; and upstream transcription factor 1. In addition, our results provide modest support for a number of candidate genes previously studied by others.

Abbreviations: CEPH, Centre d’Etude du Polymorphisme Humain; ESRD, end-stage renal disease; HBDI, Human Biological Data Interchange; SNP, single nucleotide polymorphism; STRP, simple tandem repeat polymorphism; TDT, transmission/disequilibrium test; UTR, untranslated region

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