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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

Lookup NU author(s): Dr Ana ViñuelaORCiD

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Abstract

© 2017 by the American Diabetes Association.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 plasma insulin (FI), 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 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-h 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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Author(s): Manning A, Highland HM, Gasser J, Sim X, Tukiainen T, Fontanillas P, Grarup N, Rivas MA, Mahajan A, Locke AE, Cingolani P, Pers TH, Vinuela 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, Lehtimaki T, Palotie A, Raitakari OT, Jacobs SBR, 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, de Angelis MH, 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, Syvanen A-C, Hicks PJ, Palmer ND, Ng MCY, Bowden DW, Freedman BI, Esko T, Magi 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, Muller-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, Karajamaki A, Qi Q, Qi L, Huang J, Hu FB, E Mel Ander OL, Orho-Melander M, Below JE, Aguilar D, Wong TY, U JL, Khor C-C, Chia KS, Lim WY, Cheng C-Y, Chan E, Shyong Tai E, Aung T, Linneberg A, Isomaa B, Meitinger T, Tuomi T, Hakaste L, Na Kravi C J, Jorgensen ME, Lauritzen T, Deloukas P, Stirrups KE, I Ne R Owen KH, Farmer AJ, Frayling TM, O'rahilly SP, Walker M, Levy JC, Hodgkiss D, Hattersley AT, Kuulasmaa T, Stan?cakova 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, Antero Kesaniemi Y, 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, Jorgensen 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

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2017

Volume: 66

Issue: 7

Pages: 2019-2032

Print publication date: 01/07/2017

Online publication date: 24/03/2017

Acceptance date: 13/03/2017

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association Inc.

URL: https://doi.org/10.2337/db16-1329

DOI: 10.2337/db16-1329

PubMed id: 28341696

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