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Human Molecular Genetics, 2002, Vol. 11, No. 21 2607-2614
© 2002 Oxford University Press

Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians

Francis Vasseur1,{dagger}, Nicole Helbecque2,{dagger}, Christian Dina1, Stéphane Lobbens1, Valérie Delannoy1, Stéphane Gaget1, Philippe Boutin1, Martine Vaxillaire1, Frédéric Leprêtre1, Sophie Dupont1,2,3, Kazuo Hara4, Karine Clément5, Bernard Bihain6, Takashi Kadowaki4 and Philippe Froguel1,2,3,4,5,6,7,*

1CNRS 8090, Institut de Biologie de Lille, Institut Pasteur, and CHU Lille, France, 2Service d'Epidémiologie et de Santé Publique, INSERM U.508, Institut Pasteur, Lille, France, 3Institut Supérieur d'Agriculture (ISA), Lille, France, 4Department of Metabolic Diseases, University of Tokyo, Japan, 5Service de Nutrition Hôtel Dieu, Paris, France, 6Clinical Investigation Center INSERM-CHU Nancy, Donmartin les Toul, France and 7Barts & The London Genome Centre, Queen Mary's School of Medicine, London, UK

Received June 6, 2002; Accepted July 23, 2002

Adiponectin (ACRP30), an adipocyte-secreted protein encoded by the APM1 gene, is known to modulate insulin sensitivity and glucose homeostasis, those effects protecting obese mice from diabetes. Plasma adiponectin levels correlate well with insulin sensitivity in humans, and are decreased in both type 2 diabetes (T2D) and obesity. We screened for single-nucleotide polymorphisms (SNPs) the APM1 gene coding and 5' sequences in 40 French Caucasians: 12 SNPs and 4 rare non-synonymous mutations of exon 3 were detected. The 10 most frequent SNPs were genotyped in 1373 T2D and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. The screening for rare mutations of exon 3 was extended to 1246 T2D and obese French subjects and to the members of the 148 T2D multiplex families. A haplotype including SNPs -11391 and -11377, both located in the 5' sequences, was associated with adiponectin levels (P<0.0001) and with T2D (P=0.004). The presence of at least one non-synonymous mutation in exon 3 showed evidence of association with adiponectin levels (P=0.0009) and with T2D (P=0.005). We failed to detect an association with insulin resistance indexes. Although family-based association analysis with T2D did not reach significance, our results suggest that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 contribute to the variation of the adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for T2D in the French Caucasian population.

* To whom correspondence should be addressed at: CNRS 8090, Institut Pasteur de Lille, 1 rue du Pr Calmette, 59000 Lille, France. Tel: +33 320877954; Fax: +33 320877229; Email: froguel{at}mail-good.pasteur-lille.fr

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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M Sancandi, P Griseri, B Pesce, G Patrone, F Puppo, M Lerone, G Martucciello, G Romeo, R Ravazzolo, M Devoto, et al.
Single nucleotide polymorphic alleles in the 5' region of the RET proto-oncogene define a risk haplotype in Hirschsprung's disease
J. Med. Genet., September 1, 2003; 40(9): 714 - 718.
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