New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

被引：1707

作者：

Dupuis, Josee ^{[2
,3
]}

Langenberg, Claudia ^{[4
]}

Prokopenko, Inga ^{[5
,6
]}

Saxena, Richa ^{[7
,8
]}

Soranzo, Nicole ^{[9
,10
]}

Jackson, Anne U. ^{[1
]}

Wheeler, Eleanor ^{[11
]}

Glazer, Nicole L. ^{[12
,13
]}

Bouatia-Naji, Nabila ^{[14
]}

Gloyn, Anna L. ^{[5
]}

Lindgren, Cecilia M. ^{[5
,6
]}

Magi, Reedik ^{[5
,6
]}

Morris, Andrew P. ^{[6
]}

Randall, Joshua ^{[6
]}

Johnson, Toby ^{[15
,16
,17
]}

Elliott, Paul ^{[18
,173
]}

Rybin, Denis ^{[19
]}

Thorleifsson, Gudmar ^{[20
]}

Steinthorsdottir, Valgerdur ^{[20
]}

Henneman, Peter ^{[21
]}

Grallert, Harald ^{[22
]}

Dehghan, Abbas ^{[23
]}

Hottenga, Jouke Jan ^{[24
]}

Franklin, Christopher S. ^{[25
]}

Navarro, Pau ^{[26
]}

Song, Kijoung ^{[27
]}

Goel, Anuj ^{[6
,28
]}

Perry, John R. B. ^{[29
]}

Egan, Josephine M.

Lajunen, Taina ^{[31
]}

Grarup, Niels ^{[32
]}

Sparso, Thomas ^{[32
]}

Doney, Alex ^{[33
]}

Voight, Benjamin F. ^{[7
,8
]}

Stringham, Heather M. ^{[1
]}

Li, Man ^{[34
]}

Kanoni, Stavroula ^{[35
]}

Shrader, Peter ^{[36
]}

Cavalcanti-Proenca, Christine ^{[14
]}

Kumari, Meena ^{[37
]}

Qi, Lu ^{[38
,39
]}

Timpson, Nicholas J. ^{[40
]}

Gieger, Christian ^{[22
]}

Zabena, Carina ^{[41
]}

Rocheleau, Ghislain ^{[42
,43
,44
]}

Ingelsson, Erik ^{[45
,46
]}

An, Ping ^{[47
]}

O'Connell, Jeffrey ^{[48
]}

Luan, Jian'an ^{[4
]}

Elliott, Amanda ^{[7
,8
]}

机构：

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

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

[3] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA

[4] Addenbrookes Hosp, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England

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

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

[7] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[8] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[9] Wellcome Trust Sanger Inst, Cambridge, England

[10] Kings Coll London, Twin Res & Genet Epidemiol Dept, London WC2R 2LS, England

[11] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge, England

[12] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[13] Univ Washington, Dept Med, Seattle, WA USA

[14] Univ Lille 2, Inst Pasteur, CNRS, Unite Mixte Rech 8090, Lille, France

[15] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland

[16] CHU Vaudois, Univ Inst Social & Preventat Med, CH-1011 Lausanne, Switzerland

[17] Swiss Inst Bioinformat, Lausanne, Switzerland

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

[19] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA

[20] deCODE Genet, Reykjavik, Iceland

[21] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands

[22] German Res Ctr Environm Hlth, Helmholtz Zentrum Muenchen, Inst Epidemiol, Neuherberg, Germany

[23] Erasmus Med Coll, Dept Epidemiol, Rotterdam, Netherlands

[24] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[25] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[26] Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland

[27] GlaxoSmithKline, Div Genet Res & Dev, King Of Prussia, PA USA

[28] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[29] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter, Devon, England

[30] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA

[31] Univ Oulu, Bioctr, Natl Inst Hlth & Welf, Unit Child & Adolescent Hlth & Welf, Oulu, Finland

[32] Hagedorn Res Inst, Gentofte, Denmark

[33] Univ Dundee, Ninewells Hosp & Med Sch, Dept Med & Therapeut, Level 7, Dundee DD1 9SY, Scotland

[34] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[35] Harokopio Univ, Dept Nutr Dietet, Athens, Greece

[36] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA

[37] UCL, Dept Epidemiol & Publ Hlth, London, England

[38] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[39] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[40] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England

[41] Hosp Clin San Carlos, Fdn Invest Biomed, Madrid, Spain

[42] McGill Univ, Dept Med, Montreal, PQ, Canada

[43] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

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

[45] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[46] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden

[47] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[48] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[49] Univ Lille Nord France, INSERM, U859, Lille, France

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

来源：

NATURE GENETICS | 2010年 / 42卷 / 02期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; BETA-CELL DYSFUNCTION; PLASMA-GLUCOSE; INSULIN-RESISTANCE; ESSENTIAL COMPONENTS; TRIGLYCERIDE LEVELS; MODEL ASSESSMENT; CIRCADIAN CLOCK; DISEASE RISK; FOLLOW-UP;

D O I：

10.1038/ng.520

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

引用

页码：105 / U32

页数：15

共 74 条

[1]

[Anonymous], 2007, R LANG ENV STAT COMP

[2] GenABEL: an R library for genome-wide association analysis [J].

Aulchenko, Yurii S. ;

Ripke, Stephan ;

Isaacs, Aaron ;

Van Duijn, Cornelia M. .

BIOINFORMATICS, 2007, 23 (10) :1294-1296

[3] Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts [J].

Aulchenko, Yurii S. ;

Ripatti, Samuli ;

Lindqvist, Ida ;

Boomsma, Dorret ;

Heid, Iris M. ;

Pramstaller, Peter P. ;

Penninx, Brenda W. J. H. ;

Janssens, A. Cecile J. W. ;

Wilson, James F. ;

Spector, Tim ;

Martin, Nicholas G. ;

Pedersen, Nancy L. ;

Kyvik, Kirsten Ohm ;

Kaprio, Jaakko ;

Hofman, Albert ;

Freimer, Nelson B. ;

Jarvelin, Marjo-Riitta ;

Gyllensten, Ulf ;

Campbell, Harry ;

Rudan, Igor ;

Johansson, Asa ;

Marroni, Fabio ;

Hayward, Caroline ;

Vitart, Veronique ;

Jonasson, Inger ;

Pattaro, Cristian ;

Wright, Alan ;

Hastie, Nick ;

Pichler, Irene ;

Hicks, Andrew A. ;

Falchi, Mario ;

Willemsen, Gonneke ;

Hottenga, Jouke-Jan ;

de Geus, Eco J. C. ;

Montgomery, Grant W. ;

Whitfield, John ;

Magnusson, Patrik ;

Saharinen, Juha ;

Perola, Markus ;

Silander, Kaisa ;

Isaacs, Aaron ;

Sijbrands, Eric J. G. ;

Uitterlinden, Andre G. ;

Witteman, Jacqueline C. M. ;

Oostra, Ben A. ;

Elliott, Paul ;

Ruokonen, Aimo ;

Sabatti, Chiara ;

Gieger, Christian ;

Meitinger, Thomas .

NATURE GENETICS, 2009, 41 (01) :47-55

[4] The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver [J].

Beer, Nicola L. ;

Tribble, Nicholas D. ;

McCulloch, Laura J. ;

Roos, Charlotta ;

Johnson, Paul R. V. ;

Orho-Melander, Marju ;

Gloyn, Anna L. .

HUMAN MOLECULAR GENETICS, 2009, 18 (21) :4081-4088

[5] Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin [J].

Bergman, RN ;

Zaccaro, DJ ;

Watanabe, RM ;

Haffner, SM ;

Saad, MF ;

Norris, JM ;

Wagenknecht, LE ;

Hokanson, JE ;

Rotter, JI ;

Rich, SS .

DIABETES, 2003, 52 (08) :2168-2174

[6] A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels [J].

Bouatia-Naji, Nabila ;

Rocheleau, Ghislain ;

Van Lommel, Leentje ;

Lemaire, Katleen ;

Schuit, Frans ;

Cavalcanti-Proenca, Christine ;

Marchand, Marion ;

Hartikainen, Anna-Liisa ;

Sovio, Ulla ;

De Graeve, Franck ;

Rung, Johan ;

Vaxillaire, Martine ;

Tichet, Jean ;

Marre, Michel ;

Balkau, Beverley ;

Weill, Jacques ;

Elliott, Paul ;

Jarvelin, Marjo-Riitta ;

Meyre, David ;

Polychronakos, Constantin ;

Dina, Christian ;

Sladek, Robert ;

Froguel, Philippe .

SCIENCE, 2008, 320 (5879) :1085-1088

[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] RELATIONSHIPS BETWEEN FASTING PLASMA GLUCOSE LEVELS AND INSULIN-SECRETION DURING INTRAVENOUS GLUCOSE-TOLERANCE TESTS [J].

BRUNZELL, JD ;

ROBERTSON, RP ;

LERNER, RL ;

HAZZARD, WR ;

ENSINCK, JW ;

BIERMAN, EL ;

PORTE, D .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1976, 42 (02) :222-229

[9] Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels [J].

Chen, Wei-Min ;

Erdos, Michael R. ;

Jackson, Anne U. ;

Saxena, Richa ;

Sanna, Serena ;

Silver, Kristi D. ;

Timpson, Nicholas J. ;

Hansen, Torben ;

Orru, Marco ;

Piras, Maria Grazia ;

Bonnycastle, Lori L. ;

Willer, Cristen J. ;

Lyssenko, Valeriya ;

Shen, Haiqing ;

Kuusisto, Johanna ;

Ebrahim, Shah ;

Sestu, Natascia ;

Duren, William L. ;

Spada, Maria Cristina ;

Stringham, Heather M. ;

Scott, Laura J. ;

Olla, Nazario ;

Swift, Amy J. ;

Najjar, Samer ;

Mitchell, Braxton D. ;

Lawlor, Debbie A. ;

Smith, George Davey ;

Ben-Shlomo, Yoav ;

Andersen, Gitte ;

Borch-Johnsen, Knut ;

Jorgensen, Torben ;

Saramies, Jouko ;

Valle, Timo T. ;

Buchanan, Thomas A. ;

Shuldiner, Alan R. ;

Lakatta, Edward ;

Bergman, Richard N. ;

Uda, Manuela ;

Tuomilehto, Jaakko ;

Pedersen, Oluf ;

Cao, Antonio ;

Groop, Leif ;

Mohlke, Karen L. ;

Laakso, Markku ;

Schlessinger, David ;

Collins, Francis S. ;

Altshuler, David ;

Abecasis, Goncalo R. ;

Boehnke, Michael ;

Scuteri, Angelo .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (07) :2620-2628

[10] Role of insulin-like growth factor I in maintaining normal glucose homeostasis [J].

Clemmons, DR .

HORMONE RESEARCH, 2004, 62 :77-82

← 1 2 3 4 5 6 7 8 →