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, Ghislain Rocheleau ², 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

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 ( = -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.