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

Bouatia-Naji, Nabila; Bonnefond, Amelie; Cavalcanti-Proenca, Christine; Sparso, Thomas; Holmkvist, Johan; Marchand, Marion; Delplanque, Jerome; Lobbens, Stephane; Rocheleau, Ghislain; Durand, Emmanuelle; De Graeve, Franck; Chevre, Jean-Claude; Borch-Johnsen, Knut; Hartikainen, Anna-Liisa; Ruokonen, Aimo; Tichet, Jean; Marre, Michel; Weill, Jacques; Heude, Barbara; Tauber, Maithe; Lemaire, Katleen; Schuit, Frans; Elliott, Paul; Jorgensen, Torben; Charpentier, Guillaume; Hadjadj, Samy; Cauchi, Stephane; Vaxillaire, Martine; Sladek, Robert; Visvikis-Siest, Sophie; Balkau, Beverley; Levy-Marchal, Claire; Pattou, Francois; Meyre, David; Blakemore, Alexandra IF; Jarvelin, Marjo-Riita; Walley, Andrew J; Hansen, Torben; Dina, Christian; Pedersen, Oluf; Froguel, Philippe

doi:10.1038/ng.277

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

Author:

Bouatia-Naji, Nabila

Bonnefond, Amelie ; Cavalcanti-Proenca, Christine ; Sparso, Thomas ; Holmkvist, Johan ; Marchand, Marion ; Delplanque, Jerome ; Lobbens, Stephane ; Rocheleau, Ghislain ; Durand, Emmanuelle ; De Graeve, Franck ; Chevre, Jean-Claude ; Borch-Johnsen, Knut ; Hartikainen, Anna-Liisa ; Ruokonen, Aimo ; Tichet, Jean ; Marre, Michel ; Weill, Jacques ; Heude, Barbara ; Tauber, Maithe ; Lemaire, Katleen ; Schuit, Frans ; Elliott, Paul ; Jorgensen, Torben ; Charpentier, Guillaume ; Hadjadj, Samy ; Cauchi, Stephane ; Vaxillaire, Martine ; Sladek, Robert ; Visvikis-Siest, Sophie ; Balkau, Beverley ; Levy-Marchal, Claire ; Pattou, Francois ; Meyre, David ; Blakemore, Alexandra IF ; Jarvelin, Marjo-Riita ; Walley, Andrew J ; Hansen, Torben ; Dina, Christian ; Pedersen, Oluf ; Froguel, Philippe

Keywords:

genome-wide association, insulin-resistance, gene-expression, melatonin, polymorphism, mellitus, diseases, cohort, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENOME-WIDE ASSOCIATION, INSULIN-RESISTANCE, GENE, MELATONIN, POLYMORPHISM, COHORT, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Blood Glucose, Child, Chromosomes, Human, Pair 11, Cohort Studies, Diabetes Mellitus, Type 2, Fasting, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucokinase, Humans, Insulin Resistance, Islets of Langerhans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, RNA, Messenger, Receptor, Melatonin, MT2, Receptors, Melatonin, Reproducibility of Results, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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 x 10(-7)). In European populations, the rs1387153 T allele is associated with increased FPG (beta = 0.06 mmol/l, P = 7.6 x 10(-29), N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08-1.22, P = 6.3 x 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.