New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk by Dupuis Josée, Langenberg Claudia, Prokopenko Inga, Saxena Richa, Soranzo Nicole, Jackson Anne U, Wheeler Eleanor, Glazer Nicole L, Bouatia-Naji Nabila, Gloyn Anna L, Lindgren Cecilia M, Mägi Reedik, Morris Andrew P, Randall Joshua, Johnson Toby, Elliott Paul, Rybin Denis, Thorleifsson Gudmar, Steinthorsdottir Valgerdur, Henneman Peter, Grallert Harald, Dehghan Abbas, Hottenga Jouke Jan, Franklin Christopher S, Navarro Pau, Song Kijoung, Goel Anuj, Perry John R B, Egan Josephine M, Lajunen Taina, Grarup Niels, Sparsø Thomas, Doney Alex, Voight Benjamin F, Stringham Heather M, Li Man, Kanoni Stavroula, Shrader Peter, Cavalcanti-Proença Christine, Kumari Meena, Qi Lu, Timpson Nicholas J, Gieger Christian, Zabena Carina, Rocheleau Ghislain, Ingelsson Erik, An Ping, O'Connell Jeffrey, Luan Jian'an, Elliott Amanda, McCarroll Steven A, Payne Felicity, Roccasecca Rosa Maria, Pattou François, Sethupathy Praveen, Ardlie Kristin, Ariyurek Yavuz, Balkau Beverley, Barter Philip, Beilby John P, Ben-Shlomo Yoav, Benediktsson Rafn, Bennett Amanda J, Bergmann Sven, Bochud Murielle, Boerwinkle Eric, Bonnefond Amélie, Bonnycastle Lori L, Borch-Johnsen Knut, Böttcher Yvonne, Brunner Eric, Bumpstead Suzannah J, Charpentier Guillaume, Chen Yii-Der Ida, Chines Peter, Clarke Robert, Coin Lachlan J M, Cooper Matthew N, Cornelis Marilyn, Crawford Gabe, Crisponi Laura, Day Ian N M, de Geus Eco J C, Delplanque Jerome, Dina Christian, Erdos Michael R, Fedson Annette C, Fischer-Rosinsky Antje, Forouhi Nita G, Fox Caroline S, Frants Rune, Franzosi Maria Grazia, Galan Pilar, Goodarzi Mark O, Graessler Jürgen, Groves Christopher J, Grundy Scott, Gwilliam Rhian, Gyllensten Ulf, Hadjadj Samy, Hallmans Göran, Hammond Naomi, Han Xijing, Hartikainen Anna-Liisa, Hassanali Neelam, Hayward Caroline, Heath Simon C, Hercberg Serge, Herder Christian, Hicks Andrew A, Hillman David R, Hingorani Aroon D, Hofman Albert, Hui Jennie, Hung Joe, Isomaa Bo, Johnson Paul R V, Jørgensen Torben, Jula Antti, Kaakinen Marika, Kaprio Jaakko, Kesaniemi Y Antero, Kivimaki Mika, Knight Beatrice, Koskinen Seppo, Kovacs Peter, Kyvik Kirsten Ohm, Lathrop G Mark, Lawlor Debbie A, Le Bacquer Olivier, Lecoeur Cécile, Li Yun, Lyssenko Valeriya, Mahley Robert, Mangino Massimo, Manning Alisa K, Martínez-Larrad María Teresa, McAteer Jarred B, McCulloch Laura J, McPherson Ruth, Meisinger Christa, Melzer David, Meyre David, Mitchell Braxton D, Morken Mario A, Mukherjee Sutapa, Naitza Silvia, Narisu Narisu, Neville Matthew J, Oostra Ben A, Orrù Marco, Pakyz Ruth, Palmer Colin N A, Paolisso Giuseppe, Pattaro Cristian, Pearson Daniel, Peden John F, Pedersen Nancy L, Perola Markus, Pfeiffer Andreas F H, Pichler Irene, Polasek Ozren, Posthuma Danielle, Potter Simon C, Pouta Anneli, Province Michael A, Psaty Bruce M, Rathmann Wolfgang, Rayner Nigel W, Rice Kenneth, Ripatti Samuli, Rivadeneira Fernando, Roden Michael, Rolandsson Olov, Sandbaek Annelli, Sandhu Manjinder, Sanna Serena, Sayer Avan Aihie, Scheet Paul, Scott Laura J, Seedorf Udo, Sharp Stephen J, Shields Beverley, Sigurethsson Gunnar, Sijbrands Eric J G, Silveira Angela, Simpson Laila, Singleton Andrew, Smith Nicholas L, Sovio Ulla, Swift Amy, Syddall Holly, Syvänen Ann-Christine, Tanaka Toshiko, Thorand Barbara, Tichet Jean, Tönjes Anke, Tuomi Tiinamaija, Uitterlinden André G, van Dijk Ko Willems, van Hoek Mandy, Varma Dhiraj, Visvikis-Siest Sophie, Vitart Veronique, Vogelzangs Nicole, Waeber Gérard, Wagner Peter J, Walley Andrew, Walters G Bragi, Ward Kim L, Watkins Hugh, Weedon Michael N, Wild Sarah H, Willemsen Gonneke, Witteman Jaqueline C M, Yarnell John W G, Zeggini Eleftheria, Zelenika Diana, Zethelius Björn, Zhai Guangju, Zhao Jing Hua, Zillikens M Carola, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Borecki Ingrid B, Loos Ruth J F, Meneton Pierre, Magnusson Patrik K E, Nathan David M, Williams Gordon H, Hattersley Andrew T, Silander Kaisa, Salomaa Veikko, Smith George Davey, Bornstein Stefan R, Schwarz Peter, Spranger Joachim, Karpe Fredrik, Shuldiner Alan R, Cooper Cyrus, Dedoussis George V, Serrano-Ríos Manuel, Morris Andrew D, Lind Lars, Palmer Lyle J, Hu Frank B, Franks Paul W, Ebrahim Shah, Marmot Michael, Kao W H Linda, Pankow James S, Sampson Michael J, Kuusisto Johanna, Laakso Markku, Hansen Torben, Pedersen Oluf, Pramstaller Peter Paul, Wichmann H Erich, Illig Thomas, Rudan Igor, Wright Alan F, Stumvoll Michael, Campbell Harry, Wilson James F, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Bergman Richard N, Buchanan Thomas A, Collins Francis S, Mohlke Karen L, Tuomilehto Jaakko, Valle Timo T, Altshuler David, Rotter Jerome I, Siscovick David S, Penninx Brenda W J H, Boomsma Dorret I, Deloukas Panos, Spector Timothy D, Frayling Timothy M, Ferrucci Luigi, Kong Augustine, Thorsteinsdottir Unnur, Stefansson Kari, van Duijn Cornelia M, Aulchenko Yurii S, Cao Antonio, Scuteri Angelo, Schlessinger David, Uda Manuela, Ruokonen Aimo, Jarvelin Marjo-Riitta, Waterworth Dawn M, Vollenweider Peter, Peltonen Leena, Mooser Vincent, Abecasis Goncalo R, Wareham Nicholas J, Sladek Robert, Froguel Philippe, Watanabe Richard M, Meigs James B, Groop Leif, Boehnke Michael, McCarthy Mark I, Florez Jose C, Barroso Inês in Nature genetics (2010). PubMed

Abstract

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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