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,^5,10 David Meyre,¹ Constantin Polychronakos,^2,11 Christian Dina,¹ Robert Sladek,² Philippe Froguel^1,12

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 x 10^–7) in 9353 participants. 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 (linear regression coefficient β = –0.06 millimoles per liter per A allele, combined P = 4 x 10^–23) and with pancreatic β 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 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic β cells.

¹ CNRS UMR 8090 Institute of Biology, Pasteur Institute of Lille and Lille 2 Droit et Santé University, 59019 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, Department of Molecular Cell Biology, Katholieke Universiteit, B-3000 Leuven, Belgium.
⁴ Department of Obstetrics and Gynaecology, 90014 Oulu, Finland.
⁵ Department of Epidemiology and Public Health, Imperial College, London W2 1PG, UK.
⁶ Institut Inter Régional pour la Santé (IRSA), 37520 La Riche, France.
⁷ INSERM U695, Bichat Hospital, 75722 Paris, France.
⁸ INSERM U780-IFR69, Paris Sud University, 94807 Villejuif, France.
⁹ Pediatric Endocrine Unit, Jeanne de Flandre Hospital, 59037 Lille, France.
¹⁰ Department of Public Health and General Practice, University of Oulu, 90014 Oulu, Finland.
¹¹ Department of Pediatrics, Faculty of Medicine, McGill University, Montreal H3H 1P3, Canada.
¹² Genomic Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.

^* These authors equally contributed to this work.

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

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