title: MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans.
abstract: OBJECTIVE
  Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, type 2 diabetes, or related metabolic traits.
  
  
  METHODS
  MTNR1B was sequenced in 47 probands with clinical maturity-onset diabetes of the young (MODY), in 51 probands with early-onset familial type 2 diabetes, and in 94 control individuals. Six nonsynonymous variants (G24E, L60R, V124I, R138C, R231H, and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin-induced signaling was characterized for the wild-type melatonin receptor type 1B (MT2) and the 24E, 60R, and 124I MT2 mutants in transfected COS-7 cells.
  
  
  RESULTS
  No mutations in MTNR1B were MODY specific, and none of the investigated MTNR1B variants associated with type 2 diabetes. The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10(-4)) and increased BMI (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-6)) in combined Danish and French study samples. 24E also associated with decreased FPG (beta = -0.08 mmol/l; P = 9.2 x 10(-4)) in the Danish Inter99 population. Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively.
  
  
  CONCLUSIONS
  Nonsynonymous mutations in MTNR1B are not a common cause of MODY or type 2 diabetes among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signaling does apparently not directly associate with FPG or type 2 diabetes.
authors.affiliation: Hagedorn Research Institute, Gentofte, Denmark. ehaa@hagedorn.dk
authors.forename: Ehm A
authors.initials: EA
authors.lastname: Andersson
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Thomas
authors.initials: T
authors.lastname: Sparsø
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.forename: Johan
authors.initials: J
authors.lastname: Holmkvist
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Knut
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D017668:Age of Onset; D019943:Amino Acid Substitution; D001786:Blood Glucose / Q000032:analysis*; D015992:Body Mass Index; D016022:Case-Control Studies; D002874:Chromosome Mapping; D048909:Diabetes Complications / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005215:Fasting; D014644:Genetic Variation; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics; D006801:Humans; D009765:Obesity / Q000150:complications / Q000235:genetics; D018579:Patient Selection; D040641:Quantitative Trait Loci; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D001786:Blood Glucose; D044123:Receptor, Melatonin, MT2; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2