Variants in MTNR1B influence fasting glucose levels

被引：570

作者：

Prokopenko, Inga ^{[2
,3
]}

Langenberg, Claudia ^{[4
]}

Florez, Jose C. ^{[5
,6
,7
,8
]}

Saxena, Richa ^{[5
,9
]}

Soranzo, Nicole ^{[10
,11
]}

Thorleifsson, Gudmar ^{[12
]}

Loos, Ruth J. F. ^{[4
]}

Manning, Alisa K. ^{[13
]}

Jackson, Anne U. ^{[1
]}

Aulchenko, Yurii ^{[14
]}

Potter, Simon C. ^{[10
]}

Erdos, Michael R. ^{[15
]}

Sanna, Serena ^{[16
]}

Hottenga, Jouke-Jan ^{[17
]}

Wheeler, Eleanor ^{[10
]}

Kaakinen, Marika ^{[18
]}

Lyssenko, Valeriya ^{[19
]}

Chen, Wei-Min ^{[20
,21
]}

Ahmadi, Kourosh ^{[11
]}

Beckmann, Jacques S. ^{[22
,23
]}

Bergman, Richard N. ^{[24
]}

Bochud, Murielle ^{[25
]}

Bonnycastle, Lori L. ^{[15
]}

Buchanan, Thomas A. ^{[26
]}

Cao, Antonio ^{[16
]}

Cervino, Alessandra ^{[11
]}

Coin, Lachlan ^{[27
]}

Collins, Francis S. ^{[15
]}

Crisponi, Laura ^{[16
]}

De Geus, Eco J. C. ^{[17
]}

Dehghan, Abbas ^{[14
]}

Deloukas, Panos ^{[10
]}

Doney, Alex S. F. ^{[28
]}

Elliott, Paul ^{[27
]}

Freimer, Nelson ^{[29
]}

Gateva, Vesela ^{[1
]}

Herder, Christian ^{[30
]}

Hofman, Albert ^{[14
]}

Hughes, Thomas E. ^{[31
]}

Hunt, Sarah ^{[10
]}

Illig, Thomas ^{[32
]}

Inouye, Michael ^{[10
]}

Isomaa, Bo ^{[33
]}

Johnson, Toby ^{[22
,30
]}

Kong, Augustine ^{[12
]}

Krestyaninova, Maria ^{[34
]}

Kuusisto, Johanna ^{[35
,36
]}

Laakso, Markku ^{[35
,36
]}

Lim, Noha ^{[37
]}

Lindblad, Ulf ^{[38
,39
]}

机构：

[1] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[2] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England

[3] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[4] Addenbrookes Hosp, Epidemiol Unit, MRC, Cambridge CB2 0QQ, England

[5] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[6] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[7] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA

[8] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA

[9] Massachusetts Gen Hosp, Dept Mol Biol, Ctr Human Genet Res, Boston, MA 02114 USA

[10] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[11] Kings Coll London, Twin Res & Genet Epidemiol Dept, London SE1 7EH, England

[12] deCODE Genet, IS-101 Reykjavik, Iceland

[13] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[14] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[15] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA

[16] Cittadella Univ Monserrato, CNR, INN, I-09042 Cagliari, Italy

[17] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands

[18] Univ Oulu, Inst Hlth Sci & Biocenter Oulu, Oulu 90014, Finland

[19] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[20] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA

[21] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA

[22] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland

[23] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland

[24] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA

[25] CHU Vaudois, Univ Inst Social & Prevent Med, CH-1011 Lausanne, Switzerland

[26] Univ So Calif, Keck Sch Med, Div Endocrinol, Dept Med, Los Angeles, CA 90033 USA

[27] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England

[28] Univ Dundee, Ninewells Hosp & Med Sch, Div Med & Therapeut, Diabet Res Grp, Dundee DD1 9SY, Scotland

[29] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA

[30] Univ Dusseldorf, Leibniz Inst, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany

[31] Novartis Inst BioMed Res, Diabet & Metab Dis Area, Cambridge, MA 02139 USA

[32] Helmholtz Zentrum Muenchen, Natl Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany

[33] Malmska Municipal Hlth Ctr & Hosp, Pietarsaari, Finland

[34] European Bioinformat Inst, EMBL, Hinxton, England

[35] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland

[36] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[37] Glaxo SmithKline, Med Genet Clin Pharmacol & Discovery Med, King Of Prussia, PA 19406 USA

[38] Skaraborg Inst, Skovde, Sweden

[39] Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Malmo, Sweden

[40] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[41] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Populat Pharmacogenet Grp, Dundee DD1 9SY, Scotland

[42] Oulu Univ Hosp, Dept Obstet & Gynaecol, Oulu, Finland

[43] Natl Publ Hlth Inst KLT, Dept Child & Adolescent Hlth, Oulu 90101, Finland

[44] Univ Dusseldorf, Leibniz Inst, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany

[45] Savitaipale Hlth Ctr, Savitaipale 54800, Finland

[46] Ist Patol Endocrina & Metabol, Unita Operat Geriatria, Rome, Italy

[47] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands

[48] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 GZ Groningen, Netherlands

[49] Univ Helsinki, Helsinki Univ Hosp, Dept Med, FIN-00014 Helsinki, Finland

[50] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Diabet Unit, SF-00300 Helsinki, Finland

来源：

NATURE GENETICS | 2009年 / 41卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; BETA-CELL FUNCTION; GENE-EXPRESSION; PLASMA-GLUCOSE; RISK LOCI; MELATONIN; TRIGLYCERIDE; REPLICATION; HAPLOTYPE; IMPACT;

D O I：

10.1038/ng.290

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

引用

页码：77 / 81

页数：5

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