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

Summary, in English

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.

• Författare: Josee 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 Magi; 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 Sparso; Alex Doney; Benjamin F. Voight; Heather M. Stringham; Man Li; Stavroula Kanoni; Peter Shrader; Christine Cavalcanti-Proenca; 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; Francois 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; Amelie Bonnefond; Lori L. Bonnycastle; Knut Borch-Johnsen; Yvonne Boettcher; 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; Juergen Graessler; Christopher J. Groves; Scott Grundy; Rhian Gwilliam; Ulf Gyllensten; Samy Hadjadj; Goeran 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 Jorgensen; 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; Cecile Lecoeur; Yun Li; Valeriya Lyssenko; Robert Mahley; Massimo Mangino; Alisa K. Manning; Maria Teresa Martinez-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 Orru; 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 Sigurosson; Eric J. G. Sijbrands; Angela Silveira; Laila Simpson; Andrew Singleton; Nicholas L. Smith; Ulla Sovio; Amy Swift; Holly Syddall; Ann-Christine Syvanen; Toshiko Tanaka; Barbara Thorand; Jean Tichet; Anke Tonjes; Tiinamaija Tuomi; Andre G. Uitterlinden; Ko Willems van Dijk; Mandy van Hoek; Dhiraj Varma; Sophie Visvikis-Siest; Veronique Vitart; Nicole Vogelzangs; Gerard 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; Bjorn 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-Rios; 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; Ines Barroso
• Avdelning/ar: Translationell Muskel Forskning; EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health
• Publiceringsår: 2010
• Språk: Engelska
• Sidor: 32-105
• Publikation/Tidskrift/Serie: Nature Genetics
• Volym: 42
• Issue: 2
• Länkar: http://dx.doi.org/10.1038/ng.520
• Dokumenttyp: Artikel i tidskrift
• Förlag: Nature Publishing Group
• Ämne: Endocrinology and Diabetes
• Status: Published
• Forskningsgrupp: Genomics, Diabetes and Endocrinology
• ISBN/ISSN/Övrigt: ISSN: 1546-1718