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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetes |
| Vol/bind | 66 |
| Udgave nummer | 7 |
| Sider (fra-til) | 2019-2032 |
| Antal sider | 14 |
| ISSN | 0012-1797 |
| DOI | |
| Status | Udgivet - 2017 |
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I: Diabetes, Bind 66, Nr. 7, 2017, s. 2019-2032.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
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 Hannes
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 P
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
AU - Fennell, Timothy
AU - Goldstein, Jacqueline I
AU - Grant, George B
AU - Hrabé de Angelis, Martin
AU - Maguire, Jared
AU - Neale, Benjamin M
AU - Poplin, Ryan
AU - Purcell, Shaun
AU - Schwarzmayr, Thomas
AU - Shakir, Khalid
AU - Smith, Joshua D
AU - Strom, Tim M
AU - Wieland, Thomas
AU - Lindstrom, Jaana
AU - Brandslund, Ivan
AU - Christensen, Cramer
AU - Surdulescu, Gabriela L
AU - Lakka, Timo A
AU - Doney, Alex S F
AU - Nilsson, Peter
AU - Wareham, Nicholas J
AU - Langenberg, Claudia
AU - Varga, Tibor V
AU - Franks, Paul W
AU - Rolandsson, Olov
AU - Rosengren, Anders H
AU - Farook, Vidya S
AU - Thameem, Farook
AU - Puppala, Sobha
AU - Kumar, Satish
AU - Lehman, Donna M
AU - Jenkinson, Christopher P
AU - Curran, Joanne E
AU - Hale, Daniel Esten
AU - Fowler, Sharon P
AU - Arya, Rector
AU - DeFronzo, Ralph A
AU - Abboud, Hanna E
AU - Syvänen, Ann-Christine
AU - Hicks, Pamela J
AU - Palmer, Nicholette D
AU - Ng, Maggie C Y
AU - Bowden, Donald W
AU - Freedman, Barry I
AU - Esko, Tõnu
AU - Mägi, Reedik
AU - Milani, Lili
AU - Mihailov, Evelin
AU - Metspalu, Andres
AU - Narisu, Narisu
AU - Kinnunen, Leena
AU - Bonnycastle, Lori L
AU - Swift, Amy J
AU - Pasko, Dorota
AU - Wood, Andrew R
AU - Fadista, João
AU - Pollin, Toni I
AU - Barzilai, Nir
AU - Atzmon, Gil
AU - Glaser, Benjamin
AU - Thorand, Barbara
AU - Strauch, Konstantin
AU - Peters, Annette
AU - Roden, Michael
AU - Müller-Nurasyid, Martina
AU - Liang, Liming
AU - Kriebel, Jennifer
AU - Illig, Thomas
AU - Grallert, Harald
AU - Gieger, Christian
AU - Meisinger, Christa
AU - Lannfelt, Lars
AU - Musani, Solomon K
AU - Griswold, Michael
AU - Taylor, Herman A
AU - Wilson, Gregory A
AU - Correa, Adolfo
AU - Oksa, Heikki
AU - Scott, William R
AU - Afzal, Uzma
AU - Tan, Sian-Tsung
AU - Loh, Marie
AU - Chambers, John C
AU - Sehmi, Jobanpreet
AU - Kooner, Jaspal Singh
AU - Lehne, Benjamin
AU - Cho, Yoon Shin
AU - Lee, Jong Young
AU - Han, Bok-Ghee
AU - Käräjämäki, Annemari
AU - Qi, Qibin
AU - Qi, Lu
AU - Huang, Jinyan
AU - Hu, Frank B
AU - Melander, Olle
AU - Orho-Melander, Marju
AU - Below, Jennifer E
AU - Aguilar, David
AU - Wong, Tien Yin
AU - Liu, Jianjun
AU - Khor, Chiea-Chuen
AU - Chia, Kee Seng
AU - Lim, Wei-Yen
AU - Cheng, Ching-Yu
AU - Chan, Edmund
AU - Tai, E Shyong
AU - Aung, Tin
AU - Linneberg, Allan
AU - Isomaa, Bo
AU - Meitinger, Thomas
AU - Tuomi, Tiinamaija
AU - Hakaste, Liisa
AU - Kravic, Jasmina
AU - Jørgensen, Marit E
AU - Lauritzen, Torsten
AU - Deloukas, Panos
AU - Stirrups, Kathleen E
AU - Owen, Katharine R
AU - Farmer, Andrew J
AU - Frayling, Timothy M
AU - O'Rahilly, Stephen P
AU - Walker, Mark
AU - Levy, Jonathan C
AU - Hodgkiss, Dylan
AU - Hattersley, Andrew T
AU - Kuulasmaa, Teemu
AU - Stančáková, Alena
AU - Barroso, Inês
AU - Bharadwaj, Dwaipayan
AU - Chan, Juliana C N
AU - Chandak, Giriraj R
AU - Daly, Mark J
AU - Donnelly, Peter J
AU - Ebrahim, Shah B
AU - Elliott, Paul
AU - Fingerlin, Tasha
AU - Froguel, Philippe
AU - Hu, Cheng
AU - Jia, Weiping
AU - Ma, Ronald C W
AU - McVean, Gilean
AU - Park, Taesung
AU - Prabhakaran, Dorairaj
AU - Sandhu, Manjinder
AU - Scott, James G.
AU - Sladek, Rob
AU - Tandon, Nikhil
AU - Teo, Yik Ying
AU - Zeggini, Eleftheria
AU - Watanabe, Richard M
AU - Koistinen, Heikki A
AU - Kesaniemi, Y Antero
AU - Uusitupa, Matti
AU - Spector, Timothy D
AU - Salomaa, Veikko
AU - Rauramaa, Rainer
AU - Palmer, Colin N A
AU - Prokopenko, Inga
AU - Morris, Andrew D
AU - Bergman, Richard N
AU - Collins, Francis S
AU - Lind, Lars
AU - Ingelsson, Erik
AU - Tuomilehto, Jaakko
AU - Karpe, Fredrik
AU - Groop, Leif
AU - Jørgensen, Torben
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Kuusisto, Johanna
AU - Abecasis, Gonçalo R
AU - Bell, Graeme I
AU - Blangero, John
AU - Cox, Nancy J
AU - Duggirala, Ravindranath
AU - Seielstad, Mark
AU - Wilson, James G
AU - Dupuis, Josée
AU - Ripatti, Samuli
AU - Hanis, Craig L
AU - Florez, Jose C
AU - Mohlke, Karen L
AU - Meigs, James B
AU - Laakso, Markku
AU - Morris, Andrew P
AU - Boehnke, Michael
AU - Altshuler, David
AU - McCarthy, Mark I
AU - Gloyn, Anna L
AU - Lindgren, Cecilia M
N1 - © 2017 by the American Diabetes Association.
PY - 2017
Y1 - 2017
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 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.
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 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.
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
IS - 7
ER -