MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
Common variants in the melatonin receptor type 1B (MTNR1B) locus | increase | fasting plasma glucose (FPG) | - | - | have been shown to increase | #1 |
Common variants in the melatonin receptor type 1B (MTNR1B) locus | increase | type 2 diabetes | - | - | increase the risk of | #2 |
The common 24E variant | increase | obesity | combined Danish and French study samples | odds ratio 1.20 [1.08-1.34] | associated with increased prevalence of | #3 |
The common 24E variant | increase | BMI | combined Danish and French study samples | beta = 0.5 kg/m(2) | associated with increased | #4 |
The common 24E variant | increase | waist circumference | combined Danish and French study samples | beta = 1.2 cm | associated with increased | #5 |
24E | decrease | FPG | Danish Inter99 population | beta = -0.08 mmol/l | associated with decreased | #6 |
MT2 24E mutant | decrease | constitutive activity | transfected COS-7 cells | - | Slightly decreased constitutive activity was observed for | #7 |
124I mutant | decrease | signaling | transfected COS-7 cells | - | displayed considerably decreased | #8 |
60R mutant | decrease | signaling | transfected COS-7 cells | - | displayed completely disrupted | #9 |
MTNR1B 24E | increase | body mass | - | - | associates with increased | #10 |
MTNR1B 24E | decrease | FPG | - | - | associates with decreased | #11 |
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. RESEARCH DESIGN AND 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.