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Analysis of 14 Candidate Genes for Diabetic Nephropathy on Chromosome 3q in European Populations

Strongest Evidence for Association With a Variant in the Promoter Region of the Adiponectin Gene

¹ L’Institut National de la Santé et de la Recherche Médicale (INSERM), U525, Université Pierre et Marie Curie-Paris6, Paris, France
² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
³ Centre National de Génotypage, Evry, France
⁴ Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
⁵ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
⁶ Steno Diabetes Centre, Copenhagen, Denmark
⁷ Endocrinology-Diabetology Department, INSERM ERM 324, Poitiers Hospital, Poitiers, France
⁸ Mammalian Research Council, Oxford, U.K
⁹ Department of Diabetology, Bichat Hospital, Paris, France
¹⁰ INSERM U695, Xavier Bichat University of Medicine, Paris, France

Address correspondence and reprint requests to Nathalie Vionnet, INSERM U525, Centre National de Génotypage, 2, Rue Gaston Crémieux, 91006 Evry Cedex, France. E-mail: vionnet{at}cng.fr

Abbreviations: LD, linkage disequilibrium; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test

Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66–0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03–1.32], P = 0.016; 1.46 [1.11–1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86–2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27–0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.

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