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A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk

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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Figure 1: Cumulative effects of MTNR1B rs1387153, G6PC2 rs560887, GCKR rs1260326 (P446L) and GCK rs1799884 (–30G) variants on fasting plasma glucose levels in the DESIR cohort.
Figure 2: Genomic context and association with fasting plasma glucose of rs1387153 on chromosome 11q21.
Figure 3: MTNR1B mRNA expression by a panel of human tissues and by human pancreatic islets and beta cells.

References

  1. American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care 31 (Suppl. 1), S12–S54 (2008).

  2. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20, 1183–1197 (1997).

  3. Tirosh, A. et al. Normal fasting plasma glucose levels and type 2 diabetes in young men. N. Engl. J. Med. 353, 1454–1462 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Barr, E.L. et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 116, 151–157 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Bouatia-Naji, N. et al. A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 320, 1085–1088 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Peschke, E. Melatonin, endocrine pancreas and diabetes. J. Pineal Res. 44, 26–40 (2008).

    CAS  PubMed  Google Scholar 

  7. Van Cauter, E. Putative roles of melatonin in glucose regulation. Therapie 53, 467–472 (1998).

    CAS  PubMed  Google Scholar 

  8. Boden, G., Ruiz, J., Urbain, J.L. & Chen, X. Evidence for a circadian rhythm of insulin secretion. Am. J. Physiol. 271, E246–E252 (1996).

    CAS  PubMed  Google Scholar 

  9. Peschke, E. et al. Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J. Pineal Res. 40, 135–143 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Ramracheya, R.D. et al. Function and expression of melatonin receptors on human pancreatic islets. J. Pineal Res. 44, 273–279 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Myers, A.J. et al. A survey of genetic human cortical gene expression. Nat. Genet. 39, 1494–1499 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Balkau, B. An epidemiologic survey from a network of French Health Examination Centres, (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome. Rev. Epidemiol. Sante Publique 44, 373–375 (1996).

    CAS  PubMed  Google Scholar 

  15. Visvikis-Siest, S. & Siest, G. The STANISLAS Cohort: a 10-year follow-up of supposed healthy families. Gene-environment interactions, reference values and evaluation of biomarkers in prevention of cardiovascular diseases. Clin. Chem. Lab. Med. 46, 733–747 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Heude, B. et al. Anthropometric relationships between parents and children throughout childhood: the Fleurbaix-Laventie Ville Sante Study. Int. J. Obes. (Lond) 29, 1222–1229 (2005).

    Article  CAS  Google Scholar 

  17. Hinds, D.A. et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Pritchard, J.K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Matthews, D.R. et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).

    Article  CAS  PubMed  Google Scholar 

  20. Jorgensen, T. et al. A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur. J. Cardiovasc. Prev. Rehabil. 10, 377–386 (2003).

    Article  PubMed  Google Scholar 

  21. Wallace, T.M., Levy, J.C. & Matthews, D.R. Use and abuse of HOMA modeling. Diabetes Care 27, 1487–1495 (2004).

    Article  PubMed  Google Scholar 

  22. Jarvelin, M.R. et al. Ecological and individual predictors of birthweight in a northern Finland birth cohort 1986. Paediatr. Perinat. Epidemiol. 11, 298–312 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Jaquet, D., Collin, D., Levy-Marchal, C. & Czernichow, P. Adult height distribution in subjects born small for gestational age. Horm. Res. 62, 92–96 (2004).

    CAS  PubMed  Google Scholar 

  24. Hadjadj, S. et al. Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Diabetes Care 31, 1847–1852 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lukowiak, B. et al. Identification and purification of functional human beta-cells by a new specific zinc-fluorescent probe. J. Histochem. Cytochem. 49, 519–528 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Burton, P.R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to Philippe Froguel.

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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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