A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Alisa Manning; Heather M Highland; Jessica Gasser; Xueling Sim; Taru Tukiainen; Pierre Fontanillas; Niels Grarup; Manuel A Rivas; Anubha Mahajan; Adam E Locke; Pablo Cingolani; Tune H Pers; Ana Viñuela; Andrew A Brown; Ying Wu; Jason Flannick; Christian Fuchsberger; Eric R Gamazon; Kyle J Gaulton; Hae Kyung Im; Tanya M Teslovich; Thomas W Blackwell; Jette Bork-Jensen; Noël P Burtt; Yuhui Chen; Todd Green; Christopher Hartl; Hyun Min Kang; Ashish Kumar; Claes Ladenvall; Clement Ma; Loukas Moutsianas; Richard D Pearson; John R B Perry; N William Rayner; Neil R Robertson; Laura J Scott; Martijn van de Bunt; Johan G Eriksson; Antti Jula; Seppo Koskinen; Terho Lehtimäki; Aarno Palotie; Olli T Raitakari; Suzanne Br Jacobs; Jennifer Wessel; Audrey Y Chu; Robert A Scott; Mark O Goodarzi; Christine Blancher; Gemma Buck; David Buck; Peter S Chines; Stacey Gabriel; Anette Marianne Prior Gjesing; Christopher J Groves; Mette Hollensted; Jeroen R Huyghe; Anne U Jackson; Goo Jun; Johanne Marie Justesen; Massimo Mangino; Jacquelyn Murphy; Matt Neville; Robert Onofrio; Kerrin S Small; Heather M Stringham; Joseph Trakalo; Eric Banks; Jason Carey; Mauricio O Carneiro; Mark DePristo; Yossi Farjoun; Timothy Fennell; Jacqueline I Goldstein; George Grant; Martin Hrabé de Angelis; Jared Maguire; Benjamin M Neale; Ryan Poplin; Shaun Purcell; Thomas Schwarzmayr; Khalid Shakir; Joshua D Smith; Tim M Strom; Thomas Wieland; Jaana Lindstrom; Ivan Brandslund; Cramer Christensen; Gabriela L Surdulescu; Timo A Lakka; Alex S F Doney; Peter Nilsson; Nicholas J Wareham; Claudia Langenberg; Tibor V Varga; Paul W Franks; Olov Rolandsson; Anders H Rosengren; Vidya S Farook; Farook Thameem; Sobha Puppala; Satish Kumar; Donna M Lehman; Christopher P Jenkinson; Joanne E Curran; Daniel Esten Hale; Sharon P Fowler; Rector Arya; Ralph A DeFronzo; Hanna E Abboud; Ann-Christine Syvänen; Pamela J Hicks; Nicholette D Palmer; Maggie C Y Ng; Donald W Bowden; Barry I Freedman; Tõnu Esko; Reedik Mägi; Lili Milani; Evelin Mihailov; Andres Metspalu; Narisu Narisu; Leena Kinnunen; Lori L Bonnycastle; Amy Swift; Dorota Pasko; Andrew R Wood; João Fadista; Toni I Pollin; Nir Barzilai; Gil Atzmon; Benjamin Glaser; Barbara Thorand; Konstantin Strauch; Annette Peters; Michael Roden; Martina Müller-Nurasyid; Liming Liang; Jennifer Kriebel; Thomas Illig; Harald Grallert; Christian Gieger; Christa Meisinger; Lars Lannfelt; Solomon K Musani; Michael Griswold; Herman A Taylor; Gregory Wilson; Adolfo Correa; Heikki Oksa; William R Scott; Uzma Afzal; Sian-Tsung Tan; Marie Loh; John C Chambers; Jobanpreet Sehmi; Jaspal Singh Kooner; Benjamin Lehne; Yoon Shin Cho; Jong-Young Lee; Bok-Ghee Han; Annemari Käräjämäki; Qibin Qi; Lu Qi; Jinyan Huang; Frank B Hu; Olle Melander; Marju Orho-Melander; Jennifer E Below; David Aguilar; Tien Yin Wong; Jianjun Liu; Chiea-Chuen Khor; Kee Seng Chia; Wei Yen Lim; Ching-Yu Cheng; Edmund Chan; E Shyong Tai; Tin Aung; Allan Linneberg; Bo Isomaa; Thomas Meitinger; Tiinamaija Tuomi; Liisa Hakaste; Jasmina Kravic; Marit E Jørgensen; Torsten Lauritzen; Panos Deloukas; Kathleen E Stirrups; Katharine R Owen; Andrew J Farmer; Timothy M Frayling; Stephen P O'Rahilly; Mark Walker; Jonathan C Levy; Dylan Hodgkiss; Andrew T Hattersley; Teemu Kuulasmaa; Alena Stančáková; Inês Barroso; Dwaipayan Bharadwaj; Juliana Chan; Giriraj R Chandak; Mark J Daly; Peter J Donnelly; Shah B Ebrahim; Paul Elliott; Tasha Fingerlin; Philippe Froguel; Cheng Hu; Weiping Jia; Ronald C W Ma; Gilean McVean; Taesung Park; Dorairaj Prabhakaran; Manjinder Sandhu; James Scott; Rob Sladek; Nikhil Tandon; Yik Ying Teo; Eleftheria Zeggini; Richard M Watanabe; Heikki A Koistinen; Y Antero Kesaniemi; Matti Uusitupa; Timothy D Spector; Veikko Salomaa; Rainer Rauramaa; Colin N A Palmer; Inga Prokopenko; Andrew D Morris; Richard N Bergman; Francis S Collins; Lars Lind; Erik Ingelsson; Jaakko Tuomilehto; Fredrik Karpe; Leif Groop; Torben Jørgensen; Torben Hansen; Oluf Pedersen; Johanna Kuusisto; Gonçalo Abecasis; Graeme I Bell; John Blangero; Nancy J Cox; Ravindranath Duggirala; Mark Seielstad; James G Wilson; Josee Dupuis; Samuli Ripatti; Craig L Hanis; Jose C Florez; Karen L Mohlke; James B Meigs; Markku Laakso; Andrew P Morris; Michael Boehnke; David Altshuler; Mark I McCarthy; Anna L Gloyn; Cecilia M Lindgren

doi:10.2337/db16-1329

A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Alisa Manning, Heather M Highland, Jessica Gasser, Xueling Sim, Taru Tukiainen, Pierre Fontanillas, Niels Grarup, Manuel A Rivas, Anubha Mahajan, Adam E Locke, Pablo Cingolani, Tune H Pers, Ana Viñuela, Andrew A Brown, Ying Wu, Jason Flannick, Christian Fuchsberger, Eric R Gamazon, Kyle J Gaulton, Hae Kyung ImTanya M Teslovich, Thomas W Blackwell, Jette Bork-Jensen, Noël P Burtt, Yuhui Chen, Todd Green, Christopher Hartl, Hyun Min Kang, Ashish Kumar, Claes Ladenvall, Clement Ma, Loukas Moutsianas, Richard D Pearson, John R B Perry, N William Rayner, Neil R Robertson, Laura J Scott, Martijn van de Bunt, Johan G Eriksson, Antti Jula, Seppo Koskinen, Terho Lehtimäki, Aarno Palotie, Olli T Raitakari, Suzanne Br Jacobs, Jennifer Wessel, Audrey Y Chu, Robert A Scott, Mark O Goodarzi, Christine Blancher, Gemma Buck, David Buck, Peter S Chines, Stacey Gabriel, Anette Marianne Prior Gjesing, Christopher J Groves, Mette Hollensted, Jeroen R Huyghe, Anne U Jackson, Goo Jun, Johanne Marie Justesen, Massimo Mangino, Jacquelyn Murphy, Matt Neville, Robert Onofrio, Kerrin S Small, Heather M Stringham, Joseph Trakalo, Eric Banks, Jason Carey, Mauricio O Carneiro, Mark DePristo, Yossi Farjoun, Timothy Fennell, Jacqueline I Goldstein, George Grant, Martin Hrabé de Angelis, Jared Maguire, Benjamin M Neale, Ryan Poplin, Shaun Purcell, Thomas Schwarzmayr, Khalid Shakir, Joshua D Smith, Tim M Strom, Thomas Wieland, Jaana Lindstrom, Ivan Brandslund, Cramer Christensen, Gabriela L Surdulescu, Timo A Lakka, Alex S F Doney, Peter Nilsson, Nicholas J Wareham, Claudia Langenberg, Tibor V Varga, Paul W Franks, Olov Rolandsson, Anders H Rosengren, Vidya S Farook, Farook Thameem, Sobha Puppala, Satish Kumar, Donna M Lehman, Christopher P Jenkinson, Joanne E Curran, Daniel Esten Hale, Sharon P Fowler, Rector Arya, Ralph A DeFronzo, Hanna E Abboud, Ann-Christine Syvänen, Pamela J Hicks, Nicholette D Palmer, Maggie C Y Ng, Donald W Bowden, Barry I Freedman, Tõnu Esko, Reedik Mägi, Lili Milani, Evelin Mihailov, Andres Metspalu, Narisu Narisu, Leena Kinnunen, Lori L Bonnycastle, Amy Swift, Dorota Pasko, Andrew R Wood, João Fadista, Toni I Pollin, Nir Barzilai, Gil Atzmon, Benjamin Glaser, Barbara Thorand, Konstantin Strauch, Annette Peters, Michael Roden, Martina Müller-Nurasyid, Liming Liang, Jennifer Kriebel, Thomas Illig, Harald Grallert, Christian Gieger, Christa Meisinger, Lars Lannfelt, Solomon K Musani, Michael Griswold, Herman A Taylor, Gregory Wilson, Adolfo Correa, Heikki Oksa, William R Scott, Uzma Afzal, Sian-Tsung Tan, Marie Loh, John C Chambers, Jobanpreet Sehmi, Jaspal Singh Kooner, Benjamin Lehne, Yoon Shin Cho, Jong-Young Lee, Bok-Ghee Han, Annemari Käräjämäki, Qibin Qi, Lu Qi, Jinyan Huang, Frank B Hu, Olle Melander, Marju Orho-Melander, Jennifer E Below, David Aguilar, Tien Yin Wong, Jianjun Liu, Chiea-Chuen Khor, Kee Seng Chia, Wei Yen Lim, Ching-Yu Cheng, Edmund Chan, E Shyong Tai, Tin Aung, Allan Linneberg, Bo Isomaa, Thomas Meitinger, Tiinamaija Tuomi, Liisa Hakaste, Jasmina Kravic, Marit E Jørgensen, Torsten Lauritzen, Panos Deloukas, Kathleen E Stirrups, Katharine R Owen, Andrew J Farmer, Timothy M Frayling, Stephen P O'Rahilly, Mark Walker, Jonathan C Levy, Dylan Hodgkiss, Andrew T Hattersley, Teemu Kuulasmaa, Alena Stančáková, Inês Barroso, Dwaipayan Bharadwaj, Juliana Chan, Giriraj R Chandak, Mark J Daly, Peter J Donnelly, Shah B Ebrahim, Paul Elliott, Tasha Fingerlin, Philippe Froguel, Cheng Hu, Weiping Jia, Ronald C W Ma, Gilean McVean, Taesung Park, Dorairaj Prabhakaran, Manjinder Sandhu, James Scott, Rob Sladek, Nikhil Tandon, Yik Ying Teo, Eleftheria Zeggini, Richard M Watanabe, Heikki A Koistinen, Y Antero Kesaniemi, Matti Uusitupa, Timothy D Spector, Veikko Salomaa, Rainer Rauramaa, Colin N A Palmer, Inga Prokopenko, Andrew D Morris, Richard N Bergman, Francis S Collins, Lars Lind, Erik Ingelsson, Jaakko Tuomilehto, Fredrik Karpe, Leif Groop, Torben Jørgensen, Torben Hansen, Oluf Pedersen, Johanna Kuusisto, Gonçalo Abecasis, Graeme I Bell, John Blangero, Nancy J Cox, Ravindranath Duggirala, Mark Seielstad, James G Wilson, Josee Dupuis, Samuli Ripatti, Craig L Hanis, Jose C Florez, Karen L Mohlke, James B Meigs, Markku Laakso, Andrew P Morris, Michael Boehnke, David Altshuler, Mark I McCarthy, Anna L Gloyn, Cecilia M Lindgren

Institut for Klinisk Medicin

24 Citationer (Scopus)

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 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.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	66
Sider (fra-til)	2019-2032
Antal sider	14
ISSN	0012-1797
DOI	https://doi.org/10.2337/db16-1329
Status	Udgivet - 1 jul. 2017

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10.2337/db16-1329

2019.full.pdfForlagets udgivne version, 1,92 MB

http://europepmc.org/articles/pmc5482074?pdf=renderLicens: Andet

Citationsformater

Manning, A., Highland, H. M., Gasser, J., Sim, X., Tukiainen, T., Fontanillas, P., Grarup, N., Rivas, M. A., Mahajan, A., Locke, A. E., Cingolani, P., Pers, T. H., Viñuela, A., Brown, A. A., Wu, Y., Flannick, J., Fuchsberger, C., Gamazon, E. R., Gaulton, K. J., ... Lindgren, C. M. (2017). A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. Diabetes, 66, 2019-2032. https://doi.org/10.2337/db16-1329

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, AMP, 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 2017, 'A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk', Diabetes, bind 66, s. 2019-2032. https://doi.org/10.2337/db16-1329

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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 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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note = "{\textcopyright} 2017 by the American Diabetes Association.",

year = "2017",

month = jul,

day = "1",

doi = "10.2337/db16-1329",

language = "English",

volume = "66",

pages = "2019--2032",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

}

TY - JOUR

T1 - A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

AU - Manning, Alisa

AU - Highland, Heather M

AU - Gasser, Jessica

AU - Sim, Xueling

AU - Tukiainen, Taru

AU - Fontanillas, Pierre

AU - Grarup, Niels

AU - Rivas, Manuel A

AU - Mahajan, Anubha

AU - Locke, Adam E

AU - Cingolani, Pablo

AU - Pers, Tune H

AU - Viñuela, Ana

AU - Brown, Andrew A

AU - Wu, Ying

AU - Flannick, Jason

AU - Fuchsberger, Christian

AU - Gamazon, Eric R

AU - Gaulton, Kyle J

AU - Im, Hae Kyung

AU - Teslovich, Tanya M

AU - Blackwell, Thomas W

AU - Bork-Jensen, Jette

AU - Burtt, Noël P

AU - Chen, Yuhui

AU - Green, Todd

AU - Hartl, Christopher

AU - Kang, Hyun Min

AU - Kumar, Ashish

AU - Ladenvall, Claes

AU - Ma, Clement

AU - Moutsianas, Loukas

AU - Pearson, Richard D

AU - Perry, John R B

AU - Rayner, N William

AU - Robertson, Neil R

AU - Scott, Laura J

AU - van de Bunt, Martijn

AU - Eriksson, Johan G

AU - Jula, Antti

AU - Koskinen, Seppo

AU - Lehtimäki, Terho

AU - Palotie, Aarno

AU - Raitakari, Olli T

AU - Jacobs, Suzanne Br

AU - Wessel, Jennifer

AU - Chu, Audrey Y

AU - Scott, Robert A

AU - Goodarzi, Mark O

AU - Blancher, Christine

AU - Buck, Gemma

AU - Buck, David

AU - Chines, Peter S

AU - Gabriel, Stacey

AU - Gjesing, Anette Marianne Prior

AU - Groves, Christopher J

AU - Hollensted, Mette

AU - Huyghe, Jeroen R

AU - Jackson, Anne U

AU - Jun, Goo

AU - Justesen, Johanne Marie

AU - Mangino, Massimo

AU - Murphy, Jacquelyn

AU - Neville, Matt

AU - Onofrio, Robert

AU - Small, Kerrin S

AU - Stringham, Heather M

AU - Trakalo, Joseph

AU - Banks, Eric

AU - Carey, Jason

AU - Carneiro, Mauricio O

AU - DePristo, Mark

AU - Farjoun, Yossi

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AU - Lindgren, Cecilia M

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.2337/db16-1329

DO - 10.2337/db16-1329

M3 - Journal article

C2 - 28341696

SN - 0012-1797

VL - 66

SP - 2019

EP - 2032

JO - Diabetes

JF - Diabetes

ER -

A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Abstract

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