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A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
| File | Description | Size | Format | |
|---|---|---|---|---|
 db16-1329.full.pdf | Accepted version | 6.53 MB | Adobe PDF | View/Open |
| DB161329SupplementaryData.pdf | Supporting information | 6.26 MB | Adobe PDF | View/Open |
| Title: | A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. |
| Authors: | Manning, A Highland, HM Gasser, J Sim, X Tukiainen, T Fontanillas, P Grarup, N Rivas, MA Mahajan, A Locke, AE Cingolani, P Isomaa, B Meitinger, T Tuomi, T Hakaste, L Kravic, J Jørgensen, ME Lauritzen, T Deloukas, P Stirrups, KE Im, HK Thameem, F Owen, KR Farmer, AJ Frayling, TM O'Rahilly, SP Walker, M Levy, JC Hodgkiss, D Hattersley, AT Kuulasmaa, T Stančáková, A Puppala, S Teslovich, TM Barroso, I Bharadwaj, D Chan, J Chandak, GR Daly, MJ Donnelly, PJ Ebrahim, SB Elliott, P Fingerlin, T Kumar, S Froguel, P Blackwell, TW Hu, C Jia, W Ma, RC McVean, G Park, T Prabhakaran, D Sandhu, M Scott, J Lehman, DM Sladek, R Tandon, N Bork-Jensen, J Teo, YY Zeggini, E Watanabe, RM Koistinen, HA Kesaniemi, YA Uusitupa, M Spector, TD Jenkinson, CP Salomaa, V Rauramaa, R Palmer, CN Burtt, NP Prokopenko, I Morris, AD Bergman, RN Collins, FS Lind, L Ingelsson, E Curran, JE Tuomilehto, J Karpe, F Groop, L Jørgensen, T Chen, Y Hansen, T Pedersen, O Kuusisto, J Abecasis, G Bell, GI Hale, DE Blangero, J Cox, NJ Duggirala, R Seielstad, M Wilson, JG Green, T Dupuis, J Ripatti, S Hanis, CL Florez, JC Fowler, SP Mohlke, KL Meigs, JB Laakso, M Morris, AP Boehnke, M Altshuler, D Hartl, C McCarthy, MI Gloyn, AL Lindgren, CM Arya, R Kang, HM Kumar, A Ladenvall, C Ma, C Moutsianas, L Pearson, RD Perry, JR Rayner, NW Robertson, NR Scott, LJ DeFronzo, RA Van de Bunt, M Eriksson, JG Jula, A Koskinen, S Lehtimäki, T Palotie, A Raitakari, OT Jacobs, SB Wessel, J Chu, AY Pers, TH Scott, RA Goodarzi, MO Blancher, C Buck, G Buck, D Chines, PS Gabriel, S Gjesing, AP Groves, CJ Hollensted, M Abboud, HE Huyghe, JR Jackson, AU Jun, G Justesen, JM Mangino, M Murphy, J Neville, M Onofrio, R Small, KS Stringham, HM Syvänen, AC Trakalo, J Banks, E Carey, J Carneiro, MO DePristo, M Farjoun, Y Fennell, T Goldstein, JI Grant, G Hrabé de Angelis, M Hicks, PJ Maguire, J Neale, BM Poplin, R Purcell, S Schwarzmayr, T Shakir, K Smith, JD Strom, TM Wieland, T Lindstrom, J Palmer, ND Brandslund, I Christensen, C Surdulescu, GL Lakka, TA Doney, AS Nilsson, P Wareham, NJ Langenberg, C Varga, TV Franks, PW Ng, MC Rolandsson, O Rosengren, AH Farook, VS Bowden, DW Freedman, BI Esko, T Mägi, R Milani, L Viñuela, A Mihailov, E Metspalu, A Narisu, N Kinnunen, L Bonnycastle, LL Swift, A Pasko, D Wood, AR Fadista, J Pollin, TI Brown, AA Barzilai, N Atzmon, G Glaser, B Thorand, B Strauch, K Peters, A Roden, M Müller-Nurasyid, M Liang, L Kriebel, J Wu, Y Illig, T Grallert, H Gieger, C Meisinger, C Lannfelt, L Musani, SK Griswold, M Taylor, HA Wilson, G Correa, A Flannick, J Oksa, H Scott, WR Afzal, U Tan, ST Loh, M Chambers, JC Sehmi, J Kooner, JS Lehne, B Cho, YS Fuchsberger, C Lee, JY Han, BG Käräjämäki, A Qi, Q Qi, L Huang, J Hu, FB Melander, O Orho-Melander, M Below, JE Gamazon, ER Aguilar, D Wong, TY Liu, J Khor, CC Chia, KS Lim, WY Cheng, CY Chan, E Tai, ES Aung, T Gaulton, KJ Linneberg, A |
| Item Type: | Journal Article |
| Abstract: | 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. |
| Issue Date: | 24-Mar-2017 |
| Date of Acceptance: | 13-Mar-2017 |
| URI: | http://hdl.handle.net/10044/1/46081 |
| DOI: | https://dx.doi.org/10.2337/db16-1329 |
| ISSN: | 0012-1797 |
| Publisher: | American Diabetes Association |
| Start Page: | 2019 |
| End Page: | 2032 |
| Journal / Book Title: | Diabetes |
| Volume: | 66 |
| Issue: | 7 |
| Copyright Statement: | © 2017 the American Diabetes Association. http://www.diabetesjournals.org/content/license Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. |
| Sponsor/Funder: | National Institute for Health Research Imperial College Healthcare NHS Trust- BRC Funding Medical Research Council (MRC) National Institute for Health Research Public Health England |
| Funder's Grant Number: | NF-SI-0611-10136 RDC01 79560 MR/L01341X/1 RTJ6219303-1 6509268 |
| Keywords: | Science & Technology Life Sciences & Biomedicine Endocrinology & Metabolism BETA-CELL MASS NEUROTROPHIC FACTOR GDNF FAMILY GLUCOSE-HOMEOSTASIS FATTY RAT ZDF RATS EXPRESSION SECRETION NEURTURIN MELLITUS African Americans Alleles Asian Continental Ancestry Group Case-Control Studies Diabetes Mellitus, Type 2 European Continental Ancestry Group Fasting Finland Gene Frequency Genetic Predisposition to Disease Genotype Hispanic Americans Humans Insulin Insulin Resistance Odds Ratio Proto-Oncogene Proteins c-akt 11 Medical And Health Sciences |
| Publication Status: | Published |
| Appears in Collections: | Department of Medicine (up to 2019) |