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Published Online May 1, 2008
Science DOI: 10.1126/science.1156849

Reports

Submitted on February 21, 2008
Accepted on April 3, 2008

A Polymorphism Within the G6PC2 Gene Is Associated with Fasting Plasma Glucose Levels

Nabila Bouatia-Naji 1{dagger}, Ghislain Rocheleau 2{dagger}, Leentje Van Lommel 3, Katleen Lemaire 3, Frans Schuit 3, Christine Cavalcanti-Proença 1, Marion Marchand 1, Anna-Liisa Hartikainen 4, Ulla Sovio 5, Franck De Graeve 1, Johan Rung 2, Martine Vaxillaire 1, Jean Tichet 6, Michel Marre 7, Beverley Balkau 8, Jacques Weill 9, Paul Elliott 5, Marjo-Riitta Jarvelin 10, David Meyre 1, Constantin Polychronakos 11, Christian Dina 1, Robert Sladek 2, Philippe Froguel 12*

1 CNRS UMR 8090 Institute of Biology, Pasteur Institute of Lille and Lille 2 Droit et Santé University, Lille, France.
2 Department of Human Genetics, Faculty of Medicine, McGill University and Génome Québec Innovation Centre, Montreal H3A 1A4, Canada.
3 Gene Expression Unit, Dept. Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium.
4 Department of Obstetrics and Gynaecology, Oulu, Finland.
5 Department of Epidemiology and Public Health, Imperial College, London W12 0NN, United Kingdom.
6 IRSA, La Riche, France.
7 INSERM U695, Bichat Hospital, Paris, France.
8 INSERM U780-IFR69, «Paris Sud» University, Villejuif, France.
9 Pediatric Endocrine Unit, Jeanne de Flandre Hospital, Lille, France.
10 Department of Epidemiology and Public Health, Imperial College, London W12 0NN, United Kingdom.; Department of Public Health and General Practice, University of Oulu, Finland.
11 Department of Human Genetics, Faculty of Medicine, McGill University and Génome Québec Innovation Centre, Montreal H3A 1A4, Canada.; Department of Pediatrics, Faculty of Medicine, McGill University, Montreal H3H 1P3, Canada.
12 CNRS UMR 8090 Institute of Biology, Pasteur Institute of Lille and Lille 2 Droit et Santé University, Lille, France.; Genomic Medicine, Hammersmith Hospital, Imperial College London, United Kingdom.

* To whom correspondence should be addressed.
Philippe Froguel , E-mail: p.froguel{at}imperial.ac.uk

{dagger}These authors contributed equally to this work.

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have a higher risk of mortality. To identify genetic determinants that contribute to inter-individual variation in FPG, we tested 392,935 single nucleotide polymorphisms (SNPs) in 654 normoglycemic subjects for association with FPG and we replicated the most strongly associated SNP (rs560887, p = 4 x 10-7) in 9,353 subjects. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit-related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG ({beta} = -0.06 mmol/l per A-allele, combined p = 4 x 10-23) and with pancreatic beta-cell function (Homa-B model, combined p = 3 x 10-13) in three populations; however it was not associated with type 2 diabetes risk. We speculate that G6PC2/IGRP regulates FPG by modulating the set-point for glucose-stimulated insulin secretion in pancreatic beta cells.


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