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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
Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
Univ Texas MD Anderson Canc Ctr, Human Genet Ctr, Houston, TX 77030 USA.;Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA.;Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 7, p. 2019-2032Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC , 2017. Vol. 66, no 7, p. 2019-2032
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Endocrinology and Diabetes
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URN: urn:nbn:se:uu:diva-328990DOI: 10.2337/db16-1329ISI: 000403778600030PubMedID: 28341696OAI: oai:DiVA.org:uu-328990DiVA, id: diva2:1139622
Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved

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Syvänen, Ann-ChristineLannfelt, LLind, Lars

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Grarup, NielsJustesen, Johanne MarieSyvänen, Ann-ChristineThorand, BarbaraLannfelt, LProkopenko, IngaLind, Lars
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