MTNR1B G24E Variant Associates With BMI and Fasting Plasma Glucose in the General Population in Studies of 22,142 Europeans

被引:40
作者
Andersson, Ehm A. [1 ]
Holst, Birgitte [2 ]
Sparso, Thomas [1 ]
Grarup, Niels [1 ]
Banasik, Karina [1 ]
Holmkvist, Johan [1 ]
Jorgensen, Torben [3 ,4 ]
Borch-Johnsen, Knut [5 ,6 ]
Egerod, Kristoffer L. [2 ]
Lauritzen, Torsten [7 ]
Sorensen, Thorkild I. A. [8 ]
Bonnefond, Amelie [9 ,10 ]
Meyre, David [9 ,10 ]
Froguel, Philippe [9 ,10 ,11 ]
Schwartz, Thue W. [2 ]
Pedersen, Oluf [1 ,3 ,6 ]
Hansen, Torben [1 ,12 ]
机构
[1] Hagedorn Res Inst, Gentofte, Denmark
[2] Univ Copenhagen, Mol Pharmacol Lab, Copenhagen, Denmark
[3] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark
[4] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark
[5] Steno Diabet Ctr, DK-2820 Gentofte, Denmark
[6] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark
[7] Univ Aarhus, Dept Gen Practice, Aarhus, Denmark
[8] Univ Copenhagen Hosp, Inst Prevent Med, DK-2100 Copenhagen, Denmark
[9] CNRS UMR 8090, Inst Biol, Lille, France
[10] Univ Lille 2, Inst Pasteur, Lille, France
[11] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London SW7 2AZ, England
[12] Univ So Denmark, Fac Hlth Sci, Odense, Denmark
基金
英国医学研究理事会;
关键词
PROTEIN-COUPLED RECEPTORS; MELATONIN-RECEPTOR; INCREASED RISK; POTENTIATION; EXPRESSION; RELEASE; BINDING; RATS;
D O I
10.2337/db09-1757
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 1241 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 BATT (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-5)) 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. Diabetes 59: 1539-1548, 2010
引用
收藏
页码:1539 / 1548
页数:10
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