Abstract
In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 × 10−7). In European populations, the rs1387153 T allele is associated with increased FPG (β = 0.06 mmol/l, P = 7.6 × 10−29, N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08–1.22, P = 6.3 × 10−5, cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06–1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.
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Acknowledgements
The study was supported in part by an ALFEDIAM-Les laboratoires Servier grant, the “Conseil Regional Nord-Pas-de-Calais: Fonds européen de développement économique et regional,” Genome Quebec-Genome Canada and the British Medical Research Council. N.B.-N.'s position is supported by a grant from the ANR (Agence Nationale pour la Recherche: ANR-06 PHYSIO - 037 -02). A.B. is funded by a research fellowship from the French nonprofit “Association pour l'Etude des Anomalies Congénitales.” We acknowledge funding to P.F. by the European Union (Integrated Project EURODIA LSHM-CT-2006-518153 in the Framework Programme 6 [FP06] of the European-Community). We thank M. Deweirder and F. Allegaert for DNA extraction of part of the cohorts studied; S. Gaget and S. Gallina for bioinformatics support; S. Poulain and P. Gallina for the recruitment of obese children families; B. Guardiola-Lemaitre for fruitful discussion on results; and C. Lecoeur for statistical assistance. We acknowledge the “Centre de Médecine Préventive (CMP) de Vandoeuvre-Les-Nancy” where the STANISLAS cohort was recruited. The DESIR study has been supported by INSERM, CNAMTS, Lilly, Novartis Pharma and Sanofi-Aventis, the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche and Topcon. The Diab-2-Néphrogène/Surdiagène study acknowledges the participating patients, physicians and the staff of the CIC Poitiers, PHRC (Projet Hospitalier de Recherche Clinique), and a 2003-AFD-grant. The NFBC86 is supported by the European Commission; contract number QLG1-CT-2000-01643, Biocenter, University of Oulu, Finland and the Academy of Finland. We thank L. Peltonen for providing NFBC86 DNA samples. The Inter99 study was supported by grants from the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LUCAMP), the Danish Medical Research Council, Novo Nordisk, the FOOD Study Group/the Danish Ministry of Food, Agriculture and Fisheries, the Danish Diabetes Association and the European Union (EUGENE2, grant no. LSHM-CT-2004-512013), and from the Swedish Research Council (J.H.).
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N.B.-N. was responsible for the design and data analyses, the study follow-up and the manuscript writing. A.B. was responsible for and performed the gene expression study and was involved in the genotyping of the replication stage, the gene sequencing and the manuscript writing. C.C.-P. performed the statistical analysis in the French and Finnish populations and was involved in the manuscript writing. T.S. and J.H. performed statistical analysis in the Danish samples and were involved in the manuscript writing. M. Marchand was involved in the genotyping of the replication stage, gene expression and gene sequencing. J.D. supervised the genotyping of the GWA data. S.L. and E.D. performed the GWA genotyping. G.R. and R.S. were involved in the type 2 diabetes and obesity GWA studies and the manuscript writing. F.D.G. was involved in the bioinformatics analyses for the GWA studies and the in silico eQTL analyses. J.-C.C. performed the in silico eQTL analyses. K.B.-J., A.-L.H., A.R., J.T., M. Marre, J.W., B.H., M.T., P.E., T.J., G.C., S.H., S.V.-S. and C.L.-M. provided DNA samples and phenotype data. B.B. and M.-R.J. provided DNA samples and phenotype data and were involved in the manuscript writing. T.H. and O.P. provided access to DNA samples and phenotype data, supervised the genotyping and the statistical analyses in the Danish samples and were involved in the manuscript writing. D.M. supervised the obesity GWA study. S.C. and M.V. were involved in the manuscript writing. F.P. provided the human pancreatic islets and sorted beta cells. K.L. and F.S. provided expression data in the mouse. A.I.F.B. and A.J.W. were involved in the obesity GWA study and the manuscript writing. C.D. was involved in the study design and the manuscript writing and supervised the statistical analyses. P.F. was the principal investigator of the study and was involved in the study design and the manuscript writing. All authors approved the data and the final manuscript.
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Bouatia-Naji, N., Bonnefond, A., Cavalcanti-Proença, C. et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 41, 89–94 (2009). https://doi.org/10.1038/ng.277
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DOI: https://doi.org/10.1038/ng.277
