Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes

被引：278

作者：

Bonnefond, Amelie ^{[1
,2
]}

Clement, Nathalie ^{[4
,5
]}

Fawcett, Katherine ^{[6
]}

Yengo, Loic ^{[1
,2
]}

Vaillant, Emmanuel ^{[1
,2
]}

Guillaume, Jean-Luc ^{[3
,4
,5
]}

Dechaume, Aurelie ^{[1
,2
]}

Payne, Felicity ^{[6
]}

Roussel, Ronan ^{[7
,8
]}

Czernichow, Sebastien ^{[9
,10
]}

Hercberg, Serge ^{[11
,12
]}

Hadjadj, Samy ^{[13
,14
]}

Balkau, Beverley ^{[15
,16
]}

Marre, Michel ^{[7
,8
]}

Lantieri, Olivier ^{[17
]}

Langenberg, Claudia ^{[18
]}

Bouatia-Naji, Nabila ^{[1
,2
]}

Charpentier, Guillaume ^{[19
]}

Vaxillaire, Martine ^{[1
,2
]}

Rocheleau, Ghislain ^{[20
,21
]}

Wareham, Nicholas J.

Sladek, Robert ^{[22
,23
]}

McCarthy, Mark I. ^{[24
,25
]}

Dina, Christian ^{[26
,27
,28
]}

Barroso, Ines ^{[6
,29
]}

Jockers, Ralf ^{[3
,4
,5
]}

Froguel, Philippe ^{[1
,2
,30
]}

机构：

[1] Lille Pasteur Inst, CNRS, Unite Mixte Rech UMR 8199, Lille, France

[2] Lille Nord France Univ, Ecole Doctorale Biol Sante, Lille, France

[3] Inst Cochin, INSERM, U1016, Paris, France

[4] CNRS, UMR 8104, Paris, France

[5] Paris Descartes Univ, Dept Med, Paris, France

[6] Wellcome Trust Sanger Inst, Cambridge, England

[7] Bichat Claude Bernard Univ Hosp, AP HP, Dept Endocrinol Diabetol & Nutr, Paris, France

[8] Univ Paris 07, INSERM, U695, Paris, France

[9] Ambroise Pare Hosp, AP HP, Dept Nutr, Boulogne, France

[10] Univ Versailles Saint Quentin, Unite Format & Rech UFR Sci Sante, Boulogne, France

[11] Univ Paris 13, Ctr Rech Nutr Humaine, Inst Natl Rech Agron, INSERM,U557,U1125, Bobigny, France

[12] Avicenne Hosp, AP HP, Dept Publ Hlth, Bobigny, France

[13] Ctr Hosp Univ Poitiers, Dept Endocrinol & Diabetol, Poitiers, France

[14] Clin Invest Ctr Poitiers Biotheque CIC0802, INSERM, U927, Poitiers, France

[15] Ctr Res Epidemiol & Populat Hlth, INSERM, U780, Villejuif, France

[16] Univ Paris 11, Orsay, France

[17] Inst Interreg Sante IRSA, La Riche, France

[18] Univ Cambridge, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England

[19] Corbeil Essonnes Hosp, Dept Endocrinol & Diabetol, Essonnes, France

[20] Ctr Hosp Univ Montreal, Ctr Rech, Montreal, PQ, Canada

[21] Prognomix, Montreal, PQ, Canada

[22] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ, Canada

[23] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[24] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[25] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[26] Inst Thorax, INSERM, U915, Nantes, France

[27] CNRS, Equipe Rech Labellisee 3147, Nantes, France

[28] Univ Nantes, Dept Biol Med & Hlth, Nantes, France

[29] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England

[30] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, Sch Publ Hlth, Hammersmith Hosp, London, England

来源：

NATURE GENETICS | 2012年 / 44卷 / 03期

基金：

英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; FASTING PLASMA-GLUCOSE; GENERAL-POPULATION; RISK; DISEASES; EXCESS; LOCI;

D O I：

10.1038/ng.1053

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT2) increase type 2 diabetes (T2D) risk(1,2). Although the strongest association signal was highly significant (P < 1 x 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of similar to 1.10-1.15)(1-3). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) < 0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 x 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were nonfunctional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial-or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 x 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 x 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk.

引用

页码：297 / U98

页数：7

共 29 条

[1] A method and server for predicting damaging missense mutations [J].

Adzhubei, Ivan A. ;

Schmidt, Steffen ;

Peshkin, Leonid ;

Ramensky, Vasily E. ;

Gerasimova, Anna ;

Bork, Peer ;

Kondrashov, Alexey S. ;

Sunyaev, Shamil R. .

NATURE METHODS, 2010, 7 (04) :248-249

[2] Standards of medical care in diabetes 2008 [J].

不详 .

DIABETES CARE, 2008, 31 :S12-S54

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

Andersson, Ehm A. ;

Holst, Birgitte ;

Sparso, Thomas ;

Grarup, Niels ;

Banasik, Karina ;

Holmkvist, Johan ;

Jorgensen, Torben ;

Borch-Johnsen, Knut ;

Egerod, Kristoffer L. ;

Lauritzen, Torsten ;

Sorensen, Thorkild I. A. ;

Bonnefond, Amelie ;

Meyre, David ;

Froguel, Philippe ;

Schwartz, Thue W. ;

Pedersen, Oluf ;

Hansen, Torben .

DIABETES, 2010, 59 (06) :1539-1548

[4] Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer [J].

Ayoub, MA ;

Couturier, C ;

Lucas-Meunier, E ;

Angers, S ;

Fossier, P ;

Bouvier, M ;

Jockers, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (24) :21522-21528

[5]

Balkau B, 1996, REV EPIDEMIOL SANTE, V44, P373

[6] Circadian Integration of Metabolism and Energetics [J].

Bass, Joseph ;

Takahashi, Joseph S. .

SCIENCE, 2010, 330 (6009) :1349-1354

[7] A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk [J].

Bouatia-Naji, Nabila ;

Bonnefond, Amelie ;

Cavalcanti-Proenca, Christine ;

Sparso, Thomas ;

Holmkvist, Johan ;

Marchand, Marion ;

Delplanque, Jerome ;

Lobbens, Stephane ;

Rocheleau, Ghislain ;

Durand, Emmanuelle ;

De Graeve, Franck ;

Chevre, Jean-Claude ;

Borch-Johnsen, Knut ;

Hartikainen, Anna-Liisa ;

Ruokonen, Aimo ;

Tichet, Jean ;

Marre, Michel ;

Weill, Jacques ;

Heude, Barbara ;

Tauber, Maithe ;

Lemaire, Katleen ;

Schuit, Frans ;

Elliott, Paul ;

Jorgensen, Torben ;

Charpentier, Guillaume ;

Hadjadj, Samy ;

Cauchi, Stephane ;

Vaxillaire, Martine ;

Sladek, Robert ;

Visvikis-Siest, Sophie ;

Balkau, Beverley ;

Levy-Marchal, Claire ;

Pattou, Francois ;

Meyre, David ;

Blakemore, Alexandra I. F. ;

Jarvelin, Marjo-Riita ;

Walley, Andrew J. ;

Hansen, Torben ;

Dina, Christian ;

Pedersen, Oluf ;

Froguel, Philippe .

NATURE GENETICS, 2009, 41 (01) :89-94

[8] Deep resequencing reveals excess rare recent variants consistent with explosive population growth [J].

Coventry, Alex ;

Bull-Otterson, Lara M. ;

Liu, Xiaoming ;

Clark, Andrew G. ;

Maxwell, Taylor J. ;

Crosby, Jacy ;

Hixson, James E. ;

Rea, Thomas J. ;

Muzny, Donna M. ;

Lewis, Lora R. ;

Wheeler, David A. ;

Sabo, Aniko ;

Lusk, Christine ;

Weiss, Kenneth G. ;

Akbar, Humeira ;

Cree, Andrew ;

Hawes, Alicia C. ;

Newsham, Irene ;

Varghese, Robin T. ;

Villasana, Donna ;

Gross, Shannon ;

Joshi, Vandita ;

Santibanez, Jireh ;

Morgan, Margaret ;

Chang, Kyle ;

Hale, Walker ;

Templeton, Alan R. ;

Boerwinkle, Eric ;

Gibbs, Richard ;

Sing, Charles F. .

NATURE COMMUNICATIONS, 2010, 1

[9] Reduced Expression of IFIH1 Is Protective for Type 1 Diabetes [J].

Downes, Kate ;

Pekalski, Marcin ;

Angus, Karen L. ;

Hardy, Matthew ;

Nutland, Sarah ;

Smyth, Deborah J. ;

Walker, Neil M. ;

Wallace, Chris ;

Todd, John A. .

PLOS ONE, 2010, 5 (09) :1-6

[10] International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors [J].

Dubocovich, Margarita L. ;

Delagrange, Philippe ;

Krause, Diana N. ;

Sugden, David ;

Cardinali, Daniel P. ;

Olcese, James .

PHARMACOLOGICAL REVIEWS, 2010, 62 (03) :343-380

← 1 2 3 →