| 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; Pers, TH; Viñuela, A; Brown, AA; Wu, Y; Flannick, J; Fuchsberger, C; Gamazon, ER; Gaulton, KJ; Im, HK; Teslovich, TM; Blackwell, TW; Bork-Jensen, J; Burtt, NP; Chen, Y; Green, T; Hartl, C; Kang, HM; Kumar, A; Ladenvall, C; Ma, C; Moutsianas, L; Pearson, RD; Perry, JRB; Rayner, NW; Robertson, NR; Scott, LJ; van de Bunt, M; Eriksson, JG; Jula, A; Koskinen, S; Lehtimäki, T; Palotie, A; Raitakari, OT; Jacobs, SB; Wessel, J; Chu, AY; Scott, RA; Goodarzi, MO; Blancher, C; Buck, G; Buck, D; Chines, PS; Gabriel, S; Gjesing, AP; Groves, CJ; Hollensted, M; Huyghe, JR; Jackson, AU; Jun, G; Justesen, JM; Mangino, M; Murphy, J; Neville, M; Onofrio, R; Small, KS; Stringham, HM; Trakalo, J; Banks, E; Carey, J; Carneiro, MO; DePristo, M; Farjoun, Y; Fennell, T; Goldstein, JI; Grant, G; Hrabé de Angelis, M; Maguire, J; Neale, BM; Poplin, R; Purcell, S; Schwarzmayr, T; Shakir, K; Smith, JD; Strom, TM; Wieland, T; Lindstrom, J; Brandslund, I; Christensen, C; Surdulescu, GL; Lakka, TA; Doney, ASF; Nilsson, P; Wareham, NJ; Langenberg, C; Varga, TV; Franks, PW; Rolandsson, O; Rosengren, AH; Farook, VS; Thameem, F; Puppala, S; Kumar, S; Lehman, DM; Jenkinson, CP; Curran, JE; Hale, DE; Fowler, SP; Arya, R; DeFronzo, RA; Abboud, HE; Syvänen, A-C; Hicks, PJ; Palmer, ND; Ng, MCY; Bowden, DW; Freedman, BI; Esko, T; Mägi, R; Milani, L; Mihailov, E; Metspalu, A; Narisu, N; Kinnunen, L; Bonnycastle, LL; Swift, A; Pasko, D; Wood, AR; Fadista, J; Pollin, TI; Barzilai, N; Atzmon, G; Glaser, B; Thorand, B; Strauch, K; Peters, A; Roden, M; Müller-Nurasyid, M; Liang, L; Kriebel, J; Illig, T; Grallert, H; Gieger, C; Meisinger, C; Lannfelt, L; Musani, SK; Griswold, M; Taylor, HA; Wilson, G; Correa, A; Oksa, H; Scott, WR; Afzal, U; Tan, S-T; Loh, M; Chambers, JC; Sehmi, J; Kooner, JS; Lehne, B; Cho, YS; Lee, J-Y; Han, B-G; Käräjämäki, A; Qi, Q; Qi, L; Huang, J; Hu, FB; Melander, O; Orho-Melander, M; Below, JE; Aguilar, D; Wong, TY; Liu, J; Khor, C-C; Chia, KS; Lim, WY; Cheng, C-Y; Chan, E; Tai, ES; Aung, T; Linneberg, A; Isomaa, B; Meitinger, T; Tuomi, T; Hakaste, L; Kravic, J; Jørgensen, ME; Lauritzen, T; Deloukas, P; Stirrups, KE; Owen, KR; Farmer, AJ; Frayling, TM; O'Rahilly, SP; Walker, M; Levy, JC; Hodgkiss, D; Hattersley, AT; Kuulasmaa, T; Stančáková, A; Barroso, I; Bharadwaj, D; Chan, J; Chandak, GR; Daly, MJ; Donnelly, PJ; Ebrahim, SB; Elliott, P; Fingerlin, T; Froguel, P; Hu, C; Jia, W; Ma, RCW; McVean, G; Park, T; Prabhakaran, D; Sandhu, M; Scott, J; Sladek, R; Tandon, N; Teo, YY; Zeggini, E; Watanabe, RM; Koistinen, HA; Kesaniemi, YA; Uusitupa, M; Spector, TD; Salomaa, V; Rauramaa, R; Palmer, CNA; Prokopenko, I; Morris, AD; Bergman, RN; Collins, FS; Lind, L; Ingelsson, E; Tuomilehto, J; Karpe, F; Groop, L; Jørgensen, T; Hansen, T; Pedersen, O; Kuusisto, J; Abecasis, G; Bell, GI; Blangero, J; Cox, NJ; Duggirala, R; Seielstad, M; Wilson, JG; Dupuis, J; Ripatti, S; Hanis, CL; Florez, JC; Mohlke, KL; Meigs, JB; Laakso, M; Morris, AP; Boehnke, M; Altshuler, D; McCarthy, MI; Gloyn, AL; Lindgren, CM |
| Publisher Information: |
American Diabetes Association |
| Publication Year: |
2017 |
| Collection: |
University of Exeter: Open Research Exeter (ORE) |
| Description: |
This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record. ; 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. ; We thank the more than 44,412 volunteers who participated in this study. Academy of Finland (129293,128315, 129330, 131593, 139635, 139635, 121584, 126925, 124282, and 129378, 258753); Action on Hearing Loss (G51); Ahokas Foundation; American Diabetes Association (#7-12-MN-02); Atlantic Canada Opportunities Agency; Augustinus foundation; Becket foundation; Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; Commission of the European Communities, Directorate C-Public Health (2004310); Copenhagen County; Danish Centre for Evaluation and Health Technology Assessment; Danish Council for Independent Research; Danish Heart Foundation ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.ncbi.nlm.nih.gov/pubmed/28341696; Published online 24 March 2017; http://hdl.handle.net/10871/27001; Diabetes |
| DOI: |
10.2337/db16-1329 |
| Availability: |
http://hdl.handle.net/10871/27001; https://doi.org/10.2337/db16-1329 |
| Accession Number: |
edsbas.DF1F4BBA |
| Database: |
BASE |