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Association between Angiotensin-Converting Enzyme Gene Polymorphisms and Diabetic Nephropathy: Case-Control, Haplotype, and Family-Based Study in Three European Populations

Samy Hadjadj^*, Lise Tarnow, Carol Forsblom, Gbenga Kazeem, Michel Marre^||, Per-Henrik Groop, Hans-Henrik Parving, François Cambien^¶, David A. Tregouet^¶, Ivo G. Gut^**, Alexandre Théva^¶, Dominique Gauguier, Martin Farrall, Roger Cox, Fumihiko Matsuda^**, Mark Lathrop^**, FinnDiane Study Group, Nathalie Hager-Vionnet^¶ for the EURAGEDIC (European Rational Approach for the Genetics of Diabetic Complications) Study Group

^* CHU de Poitiers, Department of Diabetology, and INSERM ERM 324, Poitiers University Hospital, Poitiers, France; Steno Diabetes Center, Copenhagen, Denmark; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, and Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland; Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; ^|| INSERM U695, Xavier Bichat University of Medicine, and Department of Diabetology, Bichat Hospital, Paris, France; ^¶ INSERM and Université Pierre et Marie Curie-Paris 6, UMR S 525, Paris, France; ^** Centre National du Genotypage, Evry, France; and Mammalian Research Council, Oxford, United Kingdom

Address correspondence to: Dr. Samy Hadjadj, Department of Diabetology, Poitiers University Hospital, BP 577, 86021 Poitiers Cedex, France. France: +33-5-49-44-39-00; Fax: +33-5-49-44-40-06; s.hadjadj{at}chu-poitiers.fr

Received for publication October 10, 2006. Accepted for publication February 2, 2007.

Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/deletion (I/D or rs1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN.

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