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

  title={New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk},
  author={Jos{\'e}e Dupuis and Claudia Langenberg and Inga Prokopenko and Richa Saxena and Nicole Soranzo and Anne U. Jackson and Eleanor Wheeler and Nicole L. Glazer and Nabila Bouatia-Naji and Anna L. Gloyn and Cecilia M. Lindgren and Reedik M{\"a}gi and Andrew P. Morris and Joshua C. Randall and Toby Johnson and Paul Elliott and Denis Rybin and Gudmar Thorleifsson and Valgerdur Steinthorsdottir and Peter Henneman and Harald Grallert and Abbas Dehghan and Jouke- Jan Hottenga and Christopher S Franklin and Pau Navarro and Kijoung Song and Anuj Goel and John R. B. Perry and Josephine M. Egan and Taina K Lajunen and Niels Grarup and Thomas Hempel Spars{\o} and Alex S. F. Doney and Benjamin F. Voight and Heather M. Stringham and Man Li and Stavroula Kanoni and Peter Shrader and Christine Cavalcanti-Proença and Meena Kumari and Lu Qi and Nicholas John Timpson and Christian Gieger and Carina Zabena and Ghislain Rocheleau and Erik Ingelsson and Ping An and Jeffrey R. O’Connell and Jian’an Luan and Amanda Elliott and Steven Mccarroll and Felicity Payne and Rosa Maria Roccasecca and François Pattou and Praveen Sethupathy and Kristin G. Ardlie and Yavuz Ariyurek and Beverley Balkau and Philip John Barter and John P. Beilby and Yoav Ben-Shlomo and Rafn Benediktsson and Amanda Bennett and S. Bergmann and Murielle Bochud and Eric Boerwinkle and Am{\'e}lie Bonnefond and Lori L Bonnycastle and Knut Borch-Johnsen and Yvonne B{\"o}ttcher and Eric J. Brunner and Suzannah J. Bumpstead and Guillaume Charpentier and Yii-der Ida Chen and Peter S. Chines and Robert J. Clarke and Lachlan J. Coin and Matthew N. Cooper and Marilyn C. Cornelis and Gabriel J Crawford and Laura Crisponi and Ian N. M. Day and Eco J. C. de Geus and J{\'e}r{\^o}me Delplanque and Christian Dina and Michael R. Erdos and Annette C. Fedson and Antje Fischer-Rosinsk{\'y} and Nita G. Forouhi and Caroline S Fox and Rune R. Frants and Maria Grazia Franzosi and Pilar Galan and Mark O. Goodarzi and Jurgen Graessler and Christopher J. Groves and Scott M. Grundy and Rhian Gwilliam and Ulf Gyllensten and Samy Hadjadj and Göran Hallmans and Naomi Hammond and Xijing Han and A-L. Hartikainen and Neelam Hassanali and Caroline Hayward and Simon C. Heath and Serge Hercberg and Christian Herder and Andrew A. Hicks and David R. Hillman and Aroon D. Hingorani and Albert Hofman and Jennie Hui and Joseph Hung and Bo Isomaa and Paul R.V. Johnson and Torben J{\o}rgensen and Antti M. Jula and Marika A Kaakinen and Jaakko A Kaprio and Y. Antero Kesaniemi and Mika Kivimaki and Beatrice A. Knight and Seppo Koskinen and Peter Kovacs and Kirsten Ohm Kyvik and G. Mark Lathrop and Deborah A. Lawlor and Olivier Le Bacquer and Cecile Lecoeur and Yun Li and Valeriya Lyssenko and Robert W. Mahley and Massimo Mangino and Alisa K. Manning and Mar{\'i}a Teresa Mart{\'i}nez-Larrad and Jarred B. McAteer and Laura J. McCulloch and Ruth McPherson and Christa Meisinger and David Melzer and David Meyre and Braxton D. Mitchell and Mario A. Morken and Sutapa Mukherjee and Silvia Naitza and Narisu Narisu and Matt J. Neville and Ben A. Oostra and Marco Orru' and Ruth E. Pakyz and Colin N. A. Palmer and Giuseppe Paolisso and Cristian Pattaro and Daniel S. Pearson and John F. Peden and Nancy L. Pedersen and Markus Perola and Andreas F. H. Pfeiffer and Irene Pichler and Ozren Pola{\vs}ek and Danielle Posthuma and Simon C. Potter and Anneli Pouta and Michael A. Province and Bruce M. Psaty and Wolfgang Rathmann and Nigel William Rayner and Kenneth M. Rice and Samuli Ripatti and Fernando Rivadeneira and Michael Roden and Olov Rolandsson and Annelli Sandbaek and Manjinder S. Sandhu and Serena Sanna and Avan Aihie Sayer and Paul Scheet and Laura J. Scott and Udo Seedorf and Stephen J. Sharp and Beverley M. Shields and Gunnar Sigurðsson and Erik J G Sijbrands and Angela Silveira and Laila Simpson and Andrew B. Singleton and Nicholas L. Smith and Ulla Sovio and Amy J. Swift and Holly E Syddall and Ann-Christine Syv{\"a}nen and Toshiko Tanaka and Barbara Thorand and Jean Tichet and Anke Tönjes and Tiinamaija Tuomi and Andr{\'e} G. Uitterlinden and Ko Willems van Dijk and Mandy van Hoek and Dhiraj Varma and Sophie Visvikis-Siest and Veronique Vitart and Nicole Vogelzangs and G{\'e}rard Waeber and Peter J Wagner and Andrew J. Walley and G. Bragi Walters and Kim L. Ward and Hugh C. Watkins and Michael N. Weedon and Sarah H. Wild and Gonneke Willemsen and Jaqueline C. M. Witteman and John W. G. Yarnell and Eleftheria Zeggini and Diana Z{\'e}l{\'e}nika and Bj{\"o}rn Zethelius and Guangju Zhai and Jing Hua Zhao and M. Carola Zillikens and Ingrid B. Borecki and Ruth J. F. Loos and Pierre Meneton and Patrik K. E. Magnusson and David M Nathan and Gordon H. Williams and Andrew T. Hattersley and Kaisa Silander and Veikko V Salomaa and George Davey Smith and Stefan R. Bornstein and Peter E H Schwarz and Joachim Spranger and Fredrik Karpe and Alan R. Shuldiner and Cyrus Cooper and George V. Dedoussis and Manuel Serrano-R{\'i}os and Andrew D. Morris and Lars Lind and Lyle J. Palmer and Frank B. Hu and Paul W. Franks and Shah Ebrahim and Michael Marmot and Wen Kao and James S. Pankow and Michael Sampson and Johanna Kuusisto and Markku Laakso and Torben Hansen and Oluf Pedersen and Peter Paul Pramstaller and Heinz-Erich Wichmann and Thomas Illig and Igor Rudan and Alan F. Wright and Michael Stumvoll and Harry Campbell and James F. Wilson and Anders Hamsten and Richard N. Bergman and Thomas A. Buchanan and Francis S. Collins and Karen L. Mohlke and Jaakko Tuomilehto and Timo T. Valle and David M Altshuler and Jerome I. Rotter and David S. Siscovick and Brenda W.J.H. Penninx and Dorret I. Boomsma and Panos Deloukas and Tim D. Spector and Timothy M. Frayling and Luigi Ferrucci and Augustine Kong and Unnur Thorsteinsd{\'o}ttir and K{\'a}ri Stef{\'a}nsson and Cornelia M. van Duijn and Yurii S. Aulchenko and Antonio Cao and Angelo Scuteri and David Schlessinger and Manuela Uda and Aimo O Ruokonen and Marjo-Riitta Jarvelin and Dawn M. Waterworth and Peter Vollenweider and Leena Peltonen and Vincent Mooser and Gonçalo R. Abecasis and Nicholas J. Wareham and Rob Sladek and Philippe Froguel and Richard M Watanabe and James B. Meigs and Leif C. Groop and Michael Boehnke and Mark I. McCarthy and Jose C. Florez and In{\^e}s Barroso},
  journal={Nature genetics},
  pages={105 - 116}
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… 

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Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels

The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

The C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS 1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.

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A comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

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The GCKR rs780094 polymorphism, or another variant with which it is in tight linkage disequilibrium, is likely to increase glucokinase regulatory protein activity to induce improved glycaemic regulation at the expense of hypertriacylglycerolaemia as reflected in the present study of 16,853 Danes.

Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

A meta-analysis of nine genome-wide association studies and a follow-up of 29 independent loci found three newly implicated loci to be associated with type 2 diabetes: GIPR, ADCY5 and VPS13C.

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

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