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 (T2D). The aims of this study were to evaluate if non-synonymous variants in MTNR1B associate with monogenic forms of hyperglycaemia, 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 T2D and in 94 control individuals. Six non-synonymous variants (G24E, L60R, V124I, R138C, R231H and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin-induced signalling was characterised for the wildtype 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 T2D. The common 24E variant associated with increased prevalence of obesity (OR=1.20 (1.08-1.34), P =8.3*10 −4 ) and increased BMI (β=0.5kg/m 2 , P =1.2*10 −5 ) and waist circumference (β=1.2cm, P =9*10 −6 ) in combined Danish and French study samples. 24E also associated with decreased FPG (β=−0.08mmol/l, P =9.2*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 signalling, respectively. Conclusions Non-synonymous mutations in MTNR1B are not a common cause of MODY or T2D among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signalling does apparently not directly associate with FPG and T2D.