MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans.
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.
Andersson
Ehm A
EA
Hagedorn Research Institute, Gentofte, Denmark. ehaa@hagedorn.dk
Holst
Birgitte
B
Sparsø
Thomas
T
Grarup
Niels
N
Banasik
Karina
K
Holmkvist
Johan
J
Jørgensen
Torben
T
Borch-Johnsen
Knut
K
Egerod
Kristoffer L
KL
Lauritzen
Torsten
T
Sørensen
Thorkild I A
TI
Bonnefond
Amélie
A
Meyre
David
D
Froguel
Philippe
P
Schwartz
Thue W
TW
Pedersen
Oluf
O
Hansen
Torben
T
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
D001786:Blood Glucose; D044123:Receptor, Melatonin, MT2; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2