Altmetric

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

File Description SizeFormat 
db16-1329.full.pdfAccepted version6.53 MBAdobe PDFView/Open
DB161329SupplementaryData.pdfSupporting information6.26 MBAdobe PDFView/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
Faculty of Medicine
Epidemiology, Public Health and Primary Care



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commonsx