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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.

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 normoglyc... Full description

Journal Title: Diabetes July 2017, Vol.66(7), pp.2019-2032
Main Author: Manning, Alisa
Other Authors: Highland, Heather M , Gasser, Jessica , Sim, Xueling , Tukiainen, Taru , Fontanillas, Pierre , Grarup, Niels , Rivas, Manuel A , Mahajan, Anubha , Locke, Adam E , Cingolani, Pablo , Pers, Tune H , Viñuela, Ana , Brown, Andrew A , Wu, Ying , Flannick, Jason , Fuchsberger, Christian , Gamazon, Eric R , Gaulton
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1939-327X ; DOI: 10.2337/db16-1329
Link: http://search.proquest.com/docview/1881268918/?pq-origsite=primo
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title: A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
format: Article
creator:
  • Manning, Alisa
  • Highland, Heather M
  • Gasser, Jessica
  • Sim, Xueling
  • Tukiainen, Taru
  • Fontanillas, Pierre
  • Grarup, Niels
  • Rivas, Manuel A
  • Mahajan, Anubha
  • Locke, Adam E
  • Cingolani, Pablo
  • Pers, Tune H
  • Viñuela, Ana
  • Brown, Andrew A
  • Wu, Ying
  • Flannick, Jason
  • Fuchsberger, Christian
  • Gamazon, Eric R
  • Gaulton
subjects:
  • African Americans–Genetics
  • Alleles–Genetics
  • Asian Continental Ancestry Group–Genetics
  • Case-Control Studies–Metabolism
  • Diabetes Mellitus, Type 2–Genetics
  • European Continental Ancestry Group–Metabolism
  • Fasting–Genetics
  • Finland–Metabolism
  • Gene Frequency–Genetics
  • Genetic Predisposition to Disease–Genetics
  • Genotype–Genetics
  • Hispanic Americans–Genetics
  • Humans–Genetics
  • Insulin–Genetics
  • Insulin Resistance–Genetics
  • Odds Ratio–Genetics
  • Proto-Oncogene Proteins C-Akt–Genetics
  • Abridged
  • Insulin
  • Akt2 Protein, Human
ispartof: Diabetes, July 2017, Vol.66(7), pp.2019-2032
description: 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.
language: eng
source:
identifier: E-ISSN: 1939-327X ; DOI: 10.2337/db16-1329
fulltext: fulltext
issn:
  • 1939327X
  • 1939-327X
url: Link


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titleA Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
creatorManning, Alisa ; Highland, Heather M ; Gasser, Jessica ; Sim, Xueling ; Tukiainen, Taru ; Fontanillas, Pierre ; Grarup, Niels ; Rivas, Manuel A ; Mahajan, Anubha ; Locke, Adam E ; Cingolani, Pablo ; Pers, Tune H ; Viñuela, Ana ; Brown, Andrew A ; Wu, Ying ; Flannick, Jason ; Fuchsberger, Christian ; Gamazon, Eric R ; Gaulton
ispartofDiabetes, July 2017, Vol.66(7), pp.2019-2032
identifierE-ISSN: 1939-327X ; DOI: 10.2337/db16-1329
subjectAfrican Americans–Genetics ; Alleles–Genetics ; Asian Continental Ancestry Group–Genetics ; Case-Control Studies–Metabolism ; Diabetes Mellitus, Type 2–Genetics ; European Continental Ancestry Group–Metabolism ; Fasting–Genetics ; Finland–Metabolism ; Gene Frequency–Genetics ; Genetic Predisposition to Disease–Genetics ; Genotype–Genetics ; Hispanic Americans–Genetics ; Humans–Genetics ; Insulin–Genetics ; Insulin Resistance–Genetics ; Odds Ratio–Genetics ; Proto-Oncogene Proteins C-Akt–Genetics ; Abridged ; Insulin ; Akt2 Protein, Human
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descriptionTo 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.
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titleA Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
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8Gene Frequency–Genetics
9Genetic Predisposition to Disease–Genetics
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12Humans–Genetics
13Insulin–Genetics
14Insulin Resistance–Genetics
15Odds Ratio–Genetics
16Proto-Oncogene Proteins C-Akt–Genetics
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titleA Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
authorManning, Alisa ; Highland, Heather M ; Gasser, Jessica ; Sim, Xueling ; Tukiainen, Taru ; Fontanillas, Pierre ; Grarup, Niels ; Rivas, Manuel A ; Mahajan, Anubha ; Locke, Adam E ; Cingolani, Pablo ; Pers, Tune H ; Viñuela, Ana ; Brown, Andrew A ; Wu, Ying ; Flannick, Jason ; Fuchsberger, Christian ; Gamazon, Eric R ; Gaulton
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5European Continental Ancestry Group–Metabolism
6Fasting–Genetics
7Finland–Metabolism
8Gene Frequency–Genetics
9Genetic Predisposition to Disease–Genetics
10Genotype–Genetics
11Hispanic Americans–Genetics
12Humans–Genetics
13Insulin–Genetics
14Insulin Resistance–Genetics
15Odds Ratio–Genetics
16Proto-Oncogene Proteins C-Akt–Genetics
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27Kang, Hyun Min
28Kumar, Ashish
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31Moutsianas, Loukas
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42Palotie, Aarno
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atitleA Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
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