Dataset Information

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

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.

SUBMITTER: Manning A

PROVIDER: S-EPMC5482074 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Low-Frequency Inactivating <i>AKT2</i> Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

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

Diabetes 20170324 7

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 <i>AKT2</i> and fasting plasma insulin (FI), a gene in which rare fully penetra ...[more]

PMID: 28341696

Similar Datasets

Project description:Finnish-specific gene variant p.P50T/AKT2 (minor allele frequency (MAF) = 1.1%) is associated with insulin resistance and increased predisposition to type 2 diabetes. Here, we have investigated in vitro the impact of the gene variant on glucose metabolism and intracellular signalling in human primary skeletal muscle cells, which were established from 14 male p.P50T/AKT2 variant carriers and 14 controls. Insulin-stimulated glucose uptake and glucose incorporation into glycogen were detected with 2-[1,2-3H]-deoxy-D-glucose and D-[14C]-glucose, respectively, and the rate of glycolysis was measured with a Seahorse XFe96 analyzer. Insulin signalling was investigated with Western blotting. The binding of variant and control AKT2-PH domains to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) was assayed using PIP StripsTM Membranes. Protein tyrosine kinase and serine-threonine kinase assays were performed using the PamGene® kinome profiling system. Insulin-stimulated glucose uptake and glycogen synthesis in myotubes in vitro were not significantly affected by the genotype. However, the insulin-stimulated glycolytic rate was impaired in variant myotubes. Western blot analysis showed that insulin-stimulated phosphorylation of AKT-Thr308, AS160-Thr642 and GSK3β-Ser9 was reduced in variant myotubes compared to controls. The binding of variant AKT2-PH domain to PI(3,4,5)P3 was reduced as compared to the control protein. PamGene® kinome profiling revealed multiple differentially phosphorylated kinase substrates, e.g. calmodulin, between the genotypes. Further in silico upstream kinase analysis predicted a large-scale impairment in activities of kinases participating, for example, in intracellular signal transduction, protein translation and cell cycle events. In conclusion, myotubes from p.P50T/AKT2 variant carriers show multiple signalling alterations which may contribute to predisposition to insulin resistance and T2D in the carriers of this signalling variant.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is caused by a combination of environmental, genetic, and epigenetic factors including, fasting blood glucose (FBG), genetic variant rs841853, and cg19693031 methylation. We evaluated the interaction between rs841853 and cg19693031 on the FBG levels of non-diabetic Taiwanese adults.MethodsWe used Taiwan Biobank (TWB) data collected between 2008 and 2016. The TWB data source contains information on basic demographics, personal lifestyles, medical history, methylation, and genotype. The study participants included 1300 people with DNA methylation data. The association of cg19693031 methylation (stratified into quartiles) with rs841853 and FBG was determined using multiple linear regression analysis. The beta-coefficients (β) and p-values were estimated.ResultsThe mean ± standard deviation (SD) of FBG in rs841853-CC individuals (92.07 ± 7.78) did not differ significantly from that in the CA + AA individuals (91.62 ± 7.14). However, the cg19693031 methylation levels were significantly different in the two groups (0.7716 ± 0.05 in CC individuals and 0.7631 ± 0.05 in CA + AA individuals (p = 0.002). The cg19693031 methylation levels according to quartiles were β < 0.738592 (< Q1), 0.738592 ≤ 0.769992 (Q1-Q2), 0.769992 ≤ 0.800918 (Q2-Q3), and β ≥ 0.800918 (≥ Q3). FBG increased with decreasing cg19693031 methylation levels in a dose-response manner (ptrend = 0.005). The β-coefficient was - 0.0236 (p = 0.965) for Q2-Q3, 1.0317 (p = 0.058) for Q1-Q2, and 1.3336 (p = 0.019 for < Q1 compared to the reference quartile (≥ Q3). The genetic variant rs841853 was not significantly associated with FBG. However, its interaction with cg19693031 methylation was significant (p-value = 0.036). Based on stratification by rs841853 genotypes, only the CC group retained the inverse and dose-response association between FBG and cg19693031 methylation. The β (p-value) was 0.8082 (0.255) for Q2-Q3, 1.6930 (0.022) for Q1-Q2, and 2.2190 (0.004) for < Q1 compared to the reference quartile (≥ Q3). The ptrend was 0.002.ConclusionSummarily, methylation at cg19693031 was inversely associated with fasting blood glucose in a dose-dependent manner. The inverse association was more prominent in rs841853-CC individuals, suggesting that rs841853 could modulate the association between cg19693031 methylation and FBG. Our results suggest that genetic variants may be involved in epigenetic mechanisms associated with FBG, a hallmark of diabetes. Therefore, integrating genetic and epigenetic data may provide more insight into the early-onset of diabetes.

Dataset Information

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Publications

A Low-Frequency Inactivating <i>AKT2</i> Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets