Accès ouvert déclaré
2017
article
A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
Benjamin M. Neale, Hanna E. Abboud, William R. Scott, Goo Jun, Paul W. Franks, Mark I. McCarthy, Dylan Hodgkiss, Vidya S. Farook, Ching‐Yu Cheng, George Grant, Weiping Jia, Todd D. Green, Christian Fuchsberger, Herman A. Taylor, Michael Griswold, Torsten Lauritzen, Markku Laakso, Richard N. Bergman, Manuel A. Rivas, James Wilson, Andres Metspalu, Robert C. Onofrio, Uzma Afzal, Maggie Ng, Mark Seielstad, Lori L. Bonnycastle, Gemma Buck, Peter M. Nilsson, Lars Lind, Jinyan Huang, Andrew T. Hattersley, Kyle J. Gaulton, Narisu Narisu, Aarno Palotie, Martina Müller‐Nurasyid, Michael Boehnke, Thomas Wieland, Eleftheria Zeggini, Jason P. Carey, Jennifer E. Below, Tune H. Pers, Michael Roden, Mark J. Daly, Mark O. Goodarzi, Shyong Tai, Ol L. E Mel Ander, Martin Hrabě de Angelis, Joshua D. Smith, Jaana Lindström, Harald Grallert, Ashish Kumar, Matt J. Neville, Gregory J. Wilson, Andrew D. Morris, Seppo K. Koskinen, Adolfo Correa, Giriraj R. Chandak, Marie Loh, Jason Flannick, Loukas Moutsianas, Ravindranath Duggirala, Barry I. Freedman, Christopher Hartl, Ronald C.W. Ma, James B. Meigs, Robert A. Scott, Benjamin Lehne, Mark Walker, Karen L. Mohlke, Ivan Brandslund, Annette Peters, Oluf Pedersen, Johan G. Eriksson, Xueling Sim, Dwaipayan Bharadwaj, J Lévy, Kat Har I Ne R. Owen, Yossi Farjoun, Richard M. Watanabe, Anne Jackson, David Aguilar, Jennifer Wessel, Claudia Langenberg, Lili Milani, Rector Arya, Thomas Meitinger, Anette P. Gjesing, Massimo Mangino, Audrey Y. Chu, Ralph A. DeFronzo, Marit E. Jørgensen, Veikko Salomaa, Manjinder S. Sandhu, Teemu Kuulasmaa, Leif Groop, Stacey Gabriel, Mauricio O. Carneiro, Dorota Pasko, Liisa Hakaste, Alex S. F. Doney, Kerrin S. Small, Kathleen Stirrups, David Altshuler, Toni I. Pollin, Leena Kinnunen, Amy J. Swift, Gonçalo R. Abecasis, Richard D. Pearson, Jacqueline I. Goldstein, Jacquelyn Murphy, Joseph Trakalo, Torben Hansen, João Fadista, Pablo Cingolani, Hae Kyung Im, Edmund Chan, Philippe Froguel, Frank B. Hu, Craig L. Hanis, Fredrik Karpe, Yik Ying Teo, Jasmi Na Kravi C, Khalid Shakir, Heikki A. Koistinen, Benjamin Gläser, Eric Banks, Jared Maguire, Liming Liang, Christopher P. Jenkinson, Josée Dupuis, Matti Uusitupa, Peter Donnelly, Jaakko Tuomilehto, Tien Yin Wong, Reedik Mägi, Tin Aung, Samuli Ripatti, Claes Ladenvall, Gil Atzmon, Ying Wu, Ana Viñuela, Timothy D. Spector, Qibin Qi, Chiea Chuen Khor, Juliana C.N. Chan, Tim M. Strom, Andrew R. Wood, John R. B. Perry, Torben Jørgensen, Eric R. Gamazon, Barbara Thorand, Stephen P. O’rahilly, Andrew Brown, Alisa K. Manning, Rainer Rauramaa, Evelin Mihailov, Jessica A. Gasser, Sobha Puppala, Cheng Hu, Mark A. DePristo, Anna L. Gloyn, Terho Lehtimäki, Allan Linneberg, Nicholas J. Wareham, Nir Barzilai, Heikki Oksa, José C. Florez, Taesung Park, Robert Sladek, Inês Barroso, Hyun Min Kang, Johanna Kuusisto, Erik Ingelsson, Tanya M. Teslovich, John Blangero, Francis S. Collins, Olov Rolandsson, Antero Kesäniemi, Christa Meisinger, Ann‐Christine Syvänen, Thomas Illig, Bok‐Ghee Han, Donna M. Lehman, Yoon Shin Cho, Andrew P. Morris, Yu‐Hui Chen, Jong‐Young Lee, Olli Raitakari, David Buck, Antti Jula, Jennifer Kriebel, J. F. Scott, Panos Deloukas, Joanne E. Curran, Jobanpreet Sehmi, Jianjun Li U, Gil McVean, Shaun Purcell, Solomon K. Musani, Tibor V. Varga, Nancy J. Cox, Bo Isomaa, Laura J. Scott, Martijn van de Bunt, Thomas W. Blackwell, Heather M. Stringham, Clement Ma, Timo A. Lakka, John C. Chambers, Tõnu Esko, Christian Gieger, Mette Hollensted, Neil R. Robertson, Peter S. Chines, Dorairaj Prabhakaran, Christopher J. Groves, Cramer Christensen, Timothy R. Fennell, Nikhil Tandon, Marju Orho‐Melander, Graeme I. Bell, Lars Lannfelt, Farook Thameem, Pierre Fontanillas, Jeroen R. Huyghe, Gabriela L. Surdulescu, Jaspal S. Kooner, Kee Seng Chia, Sharon P. Fowler, Nigel W. Rayner, Niels Grarup, Inga Prokopenko, Daniel E. Hale, Paul Elliott, Shah B. Ebrahim, Christine Blancher, Wei Yen Lim, Suzanne B.R. Jacobs, Annemari Käräjämäki, Anubha Mahajan, Cecilia M. Lindgren, Taru Tukiainen, Adam E. Locke, Donald W. Bowden, Johanne Marie Justesen, Timothy M. Frayling, Heather M. Highland, Jette Bork‐Jensen, Anders H. Rosengren, Alena Stan cáková, Satish Kumar, Noël P. Burtt, Konstantin Strauch, Lu Qi, Thomas Schwarzmayr, Ryan Poplin, Tasha E. Fingerlin
9Citations signalées, ce qui n’est pas une note de qualité
3Institutions déclarées
2Pays d’affiliation déclarés
Rattachement africain : in, us.
Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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Les sujets associés
Cardiovascular Function and Risk Factors