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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

Sim, Xueling ; Grarup, Niels ; Locke, Adam E ; Wu, Ying ; Blackwell, Thomas W ; Chen, Yuhui ; Kang, Hyun Min ; Kumar, Ashish ; Rayner, N William ; van de Bunt, Martijn ; Koskinen, Seppo ; Palotie, Aarno ; Raitakari, Olli T ; Jacobs, Suzanne B R ; Wessel, Jennifer ; Buck, Gemma ; Chines, Peter S ; Gabriel, Stacey ; Hollensted, Mette ; Justesen, Johanne Marie ; Mangino, Massimo ; Murphy, Jacquelyn ; Trakalo, Joseph ; Banks, Eric ; DePristo, Mark ; Grant, George ; Hrabé de Angelis, Martin ; Poplin, Ryan ; Shakir, Khalid ; Strom, Tim M ; Surdulescu, Gabriela L ; Lakka, Timo A ; Wareham, Nicholas J ; Varga, Tibor V ; Franks, Paul W ; Rosengren, Anders H ; Thameem, Farook ; Kumar, Satish ; Arya, Rector ; DeFronzo, Ralph A ; Syvänen, Ann-Christine ; Palmer, Nicholette D ; Bowden, Donald W ; Mägi, Reedik ; Kinnunen, Leena ; Swift, Amy ; Pasko, Dorota ; Fadista, João ; Barzilai, Nir ; Atzmon, Gil ; Glaser, Benjamin ; Roden, Michael ; Liang, Liming ; Musani, Solomon K ; Griswold, Michael ; Taylor, Jr, Herman A ; Wilson, Sr, Gregory ; Loh, Marie ; Chambers, John C ; Kooner, Jaspal Singh ; Lehne, Benjamin ; Cho, Yoon Shin ; Lee, Jong-Young ; Qi, Lu ; Liu, Jianjun ; Chia, Kee Seng ; Lim, Wei Yen ; Cheng, Ching-Yu ; Chan, Edmund ; Aung, Tin ; Isomaa, Bo ; Hakaste, Liisa ; Kravic, Jasmina ; Frayling, Timothy M ; O'Rahilly, Stephen P ; Levy, Jonathan C ; Kuulasmaa, Teemu ; Stančáková, Alena ; Barroso, Inês ; Bharadwaj, Dwaipayan ; Chandak, Giriraj R ; Daly, Mark J ; Donnelly, Peter J ; Ebrahim, Shah B ; Elliott, Paul ; Hu, Cheng ; McVean, Gilean ; Teo, Yik Ying ; Zeggini, Eleftheria ; Spector, Timothy D ; Morris, Andrew D ; Lind, Lars ; Groop, Leif ; Abecasis, Gonçalo ; Bell, Graeme I ; Blangero, John ; Dupuis, Josee ; Meigs, James B ; Morris, Andrew P ; Lindgren, Cecilia M

Diabetes (New York, N.Y.), 2017-07, Vol.66 (7), p.2019-2032 [Periódico revisado por pares]

United States: American Diabetes Association

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Título:
A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
Autor: Sim, Xueling ; Grarup, Niels ; Locke, Adam E ; Wu, Ying ; Blackwell, Thomas W ; Chen, Yuhui ; Kang, Hyun Min ; Kumar, Ashish ; Rayner, N William ; van de Bunt, Martijn ; Koskinen, Seppo ; Palotie, Aarno ; Raitakari, Olli T ; Jacobs, Suzanne B R ; Wessel, Jennifer ; Buck, Gemma ; Chines, Peter S ; Gabriel, Stacey ; Hollensted, Mette ; Justesen, Johanne Marie ; Mangino, Massimo ; Murphy, Jacquelyn ; Trakalo, Joseph ; Banks, Eric ; DePristo, Mark ; Grant, George ; Hrabé de Angelis, Martin ; Poplin, Ryan ; Shakir, Khalid ; Strom, Tim M ; Surdulescu, Gabriela L ; Lakka, Timo A ; Wareham, Nicholas J ; Varga, Tibor V ; Franks, Paul W ; Rosengren, Anders H ; Thameem, Farook ; Kumar, Satish ; Arya, Rector ; DeFronzo, Ralph A ; Syvänen, Ann-Christine ; Palmer, Nicholette D ; Bowden, Donald W ; Mägi, Reedik ; Kinnunen, Leena ; Swift, Amy ; Pasko, Dorota ; Fadista, João ; Barzilai, Nir ; Atzmon, Gil ; Glaser, Benjamin ; Roden, Michael ; Liang, Liming ; Musani, Solomon K ; Griswold, Michael ; Taylor, Jr, Herman A ; Wilson, Sr, Gregory ; Loh, Marie ; Chambers, John C ; Kooner, Jaspal Singh ; Lehne, Benjamin ; Cho, Yoon Shin ; Lee, Jong-Young ; Qi, Lu ; Liu, Jianjun ; Chia, Kee Seng ; Lim, Wei Yen ; Cheng, Ching-Yu ; Chan, Edmund ; Aung, Tin ; Isomaa, Bo ; Hakaste, Liisa ; Kravic, Jasmina ; Frayling, Timothy M ; O'Rahilly, Stephen P ; Levy, Jonathan C ; Kuulasmaa, Teemu ; Stančáková, Alena ; Barroso, Inês ; Bharadwaj, Dwaipayan ; Chandak, Giriraj R ; Daly, Mark J ; Donnelly, Peter J ; Ebrahim, Shah B ; Elliott, Paul ; Hu, Cheng ; McVean, Gilean ; Teo, Yik Ying ; Zeggini, Eleftheria ; Spector, Timothy D ; Morris, Andrew D ; Lind, Lars ; Groop, Leif ; Abecasis, Gonçalo ; Bell, Graeme I ; Blangero, John ; Dupuis, Josee ; Meigs, James B ; Morris, Andrew P ; Lindgren, Cecilia M
Assuntos: African American ; African Americans ; African Americans - genetics ; AKT1 protein ; AKT2 protein ; AKT2 protein, human ; AKT3 protein ; allele ; Alleles ; Asian continental ancestry group ; Asians - genetics ; case control study ; Case-Control Studies ; Caucasian ; cell function ; Clinical Medicine ; controlled study ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 ; Diabetes Mellitus, Type 2 - genetics ; Diabetes Mellitus, Type 2 - metabolism ; diet restriction ; Endocrinology and Diabetes ; Endokrinologi och diabetes ; European Continental Ancestry Group ; Fasting ; Fasting - metabolism ; Finland ; Finn (citizen) ; gene expression ; Gene Frequency ; gene inactivation ; gene mutation ; genetic association ; genetic predisposition ; Genetic Predisposition to Disease ; genetic risk ; genetic susceptibility ; genetic variability ; genetics ; Genetics/Genomes/Proteomics/Metabolomics ; Genotype ; Genotype & phenotype ; Genotyping ; Glucose ; glucose homeostasis ; glycemic control ; Hispanic ; Hispanic Americans ; Hispanic or Latino - genetics ; Homeostasis ; Homology ; human ; human cell ; Humans ; in vitro study ; Insulin ; Insulin - metabolism ; insulin blood level ; insulin resistance ; Insulin Resistance - genetics ; insulin sensitivity ; Klinisk medicin ; major clinical study ; Medical and Health Sciences ; Medicin och hälsovetenskap ; messenger RNA ; metabolism ; monogenic disorder ; Mutation ; mutational analysis ; non insulin dependent diabetes mellitus ; Odds Ratio ; penetrance ; phenotype ; Pleckstrin ; pleckstrin homology domain ; priority journal ; protein expression ; protein function ; protein kinase B ; protein kinase B beta ; protein phosphorylation ; protein serine threonine kinase ; Proteins ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-akt - genetics ; Risk assessment ; RNA sequence ; single nucleotide polymorphism ; unclassified drug ; Whites - genetics ; whole exome sequencing
É parte de: Diabetes (New York, N.Y.), 2017-07, Vol.66 (7), p.2019-2032
Notas: A.L.G. and C.M.L. jointly directed this research. A.Man., H.M.H., J.G., X.S., T.Tuk., and P.Fo. contributed equally to this work.
Descrição: 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 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 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of .
Editor: United States: American Diabetes Association
Idioma: Inglês

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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

United States: American Diabetes Association

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