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

Authors:
Josée Dupuis Claudia Langenberg Inga Prokopenko Richa Saxena Nicole Soranzo Anne U Jackson Eleanor Wheeler Nicole L Glazer Nabila Bouatia-Naji Anna L Gloyn Cecilia M Lindgren Reedik Mägi Andrew P Morris Joshua Randall Toby Johnson Paul Elliott Denis Rybin Gudmar Thorleifsson Valgerdur Steinthorsdottir Peter Henneman Harald Grallert Abbas Dehghan Jouke Jan Hottenga Christopher S Franklin Pau Navarro Kijoung Song Anuj Goel John R B Perry Josephine M Egan Taina Lajunen Niels Grarup Thomas Sparsø Alex Doney Benjamin F Voight Heather M Stringham Man Li Stavroula Kanoni Peter Shrader Christine Cavalcanti-Proença Meena Kumari Lu Qi Nicholas J Timpson Christian Gieger Carina Zabena Ghislain Rocheleau Erik Ingelsson Ping An Jeffrey O'Connell Jian'an Luan Amanda Elliott Steven A McCarroll Felicity Payne Rosa Maria Roccasecca François Pattou Praveen Sethupathy Kristin Ardlie Yavuz Ariyurek Beverley Balkau Philip Barter John P Beilby Yoav Ben-Shlomo Rafn Benediktsson Amanda J Bennett Sven Bergmann Murielle Bochud Eric Boerwinkle Amélie Bonnefond Lori L Bonnycastle Knut Borch-Johnsen Yvonne Böttcher Eric Brunner Suzannah J Bumpstead Guillaume Charpentier Yii-Der Ida Chen Peter Chines Robert Clarke Lachlan J M Coin Matthew N Cooper Marilyn Cornelis Gabe Crawford Laura Crisponi Ian N M Day Eco J C de Geus Jerome Delplanque Christian Dina Michael R Erdos Annette C Fedson Antje Fischer-Rosinsky Nita G Forouhi Caroline S Fox Rune Frants Maria Grazia Franzosi Pilar Galan Mark O Goodarzi Jürgen Graessler Christopher J Groves Scott Grundy Rhian Gwilliam Ulf Gyllensten Samy Hadjadj Göran Hallmans Naomi Hammond Xijing Han Anna-Liisa Hartikainen Neelam Hassanali Caroline Hayward Simon C Heath Serge Hercberg Christian Herder Andrew A Hicks David R Hillman Aroon D Hingorani Albert Hofman Jennie Hui Joe Hung Bo Isomaa Paul R V Johnson Torben Jørgensen Antti Jula Marika Kaakinen Jaakko Kaprio Y Antero Kesaniemi Mika Kivimaki Beatrice Knight Seppo Koskinen Peter Kovacs Kirsten Ohm Kyvik G Mark Lathrop Debbie A Lawlor Olivier Le Bacquer Cécile Lecoeur Yun Li Valeriya Lyssenko Robert Mahley Massimo Mangino Alisa K Manning María Teresa Martínez-Larrad Jarred B McAteer Laura J McCulloch Ruth McPherson Christa Meisinger David Melzer David Meyre Braxton D Mitchell Mario A Morken Sutapa Mukherjee Silvia Naitza Narisu Narisu Matthew J Neville Ben A Oostra Marco Orrù Ruth Pakyz Colin N A Palmer Giuseppe Paolisso Cristian Pattaro Daniel Pearson John F Peden Nancy L Pedersen Markus Perola Andreas F H Pfeiffer Irene Pichler Ozren Polasek Danielle Posthuma Simon C Potter Anneli Pouta Michael A Province Bruce M Psaty Wolfgang Rathmann Nigel W Rayner Kenneth Rice Samuli Ripatti Fernando Rivadeneira Michael Roden Olov Rolandsson Annelli Sandbaek Manjinder Sandhu Serena Sanna Avan Aihie Sayer Paul Scheet Laura J Scott Udo Seedorf Stephen J Sharp Beverley Shields Gunnar Sigurethsson Eric J G Sijbrands Angela Silveira Laila Simpson Andrew Singleton Nicholas L Smith Ulla Sovio Amy Swift Holly Syddall Ann-Christine Syvänen Toshiko Tanaka Barbara Thorand Jean Tichet Anke Tönjes Tiinamaija Tuomi André G Uitterlinden Ko Willems van Dijk Mandy van Hoek Dhiraj Varma Sophie Visvikis-Siest Veronique Vitart Nicole Vogelzangs Gérard Waeber Peter J Wagner Andrew Walley G Bragi Walters Kim L Ward Hugh Watkins Michael N Weedon Sarah H Wild Gonneke Willemsen Jaqueline C M Witteman John W G Yarnell Eleftheria Zeggini Diana Zelenika Björn Zethelius Guangju Zhai Jing Hua Zhao M Carola Zillikens Ingrid B Borecki Ruth J F Loos Pierre Meneton Patrik K E Magnusson David M Nathan Gordon H Williams Andrew T Hattersley Kaisa Silander Veikko Salomaa George Davey Smith Stefan R Bornstein Peter Schwarz Joachim Spranger Fredrik Karpe Alan R Shuldiner Cyrus Cooper George V Dedoussis Manuel Serrano-Ríos Andrew D Morris Lars Lind Lyle J Palmer Frank B Hu Paul W Franks Shah Ebrahim Michael Marmot W H Linda Kao James S Pankow Michael J Sampson Johanna Kuusisto Markku Laakso Torben Hansen Oluf Pedersen Peter Paul Pramstaller H Erich Wichmann Thomas Illig Igor Rudan Alan F Wright Michael Stumvoll Harry Campbell James F Wilson Richard N Bergman Thomas A Buchanan Francis S Collins Karen L Mohlke Jaakko Tuomilehto Timo T Valle David Altshuler Jerome I Rotter David S Siscovick Brenda W J H Penninx Dorret I Boomsma Panos Deloukas Timothy D Spector Timothy M Frayling Luigi Ferrucci Augustine Kong Unnur Thorsteinsdottir Kari Stefansson Cornelia M van Duijn Yurii S Aulchenko Antonio Cao Angelo Scuteri David Schlessinger Manuela Uda Aimo Ruokonen Marjo-Riitta Jarvelin Dawn M Waterworth Peter Vollenweider Leena Peltonen Vincent Mooser Goncalo R Abecasis Nicholas J Wareham Robert Sladek Philippe Froguel Richard M Watanabe James B Meigs Leif Groop Michael Boehnke Mark I McCarthy Jose C Florez Inês Barroso

Nat Genet 2010 Feb 17;42(2):105-16. Epub 2010 Jan 17.

Department of Biostatistics, Boston University School of Public Health, Massachusetts, USA.

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.

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http://www.nature.com/articles/ng.520
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http://dx.doi.org/10.1038/ng.520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018764PMC
February 2010
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