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Olle Melander

Principal investigator

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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

Author

  • Alisa Manning
  • Claes Ladenvall
  • Peter Nilsson
  • Tibor V. Varga
  • Paul Franks
  • Anders Rosengren
  • Olle Melander
  • Marju Orho-Melander
  • Jasmina Kravic
  • Leif Groop
  • Cecilia M. Lindgren

Summary, in English

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. © 2017 by the American Diabetes Association.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Internal Medicine - Epidemiology
  • EpiHealth: Epidemiology for Health
  • Genetic and Molecular Epidemiology
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Diabetes - Islet Patophysiology
  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease
  • Diabetic Complications

Publishing year

2017

Language

English

Pages

2019-2032

Publication/Series

Diabetes

Volume

66

Issue

7

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Keywords

  • AKT1 protein
  • AKT3 protein
  • glucose
  • insulin
  • messenger RNA
  • protein kinase B beta
  • protein serine threonine kinase
  • unclassified drug
  • AKT2 protein, human
  • protein kinase B
  • Article
  • cell function
  • controlled study
  • diet restriction
  • Finland
  • Finn (citizen)
  • gene expression
  • gene frequency
  • gene inactivation
  • gene mutation
  • genetic association
  • genetic risk
  • genetic susceptibility
  • genetic variability
  • genotype
  • glucose homeostasis
  • glycemic control
  • human
  • human cell
  • in vitro study
  • insulin blood level
  • insulin sensitivity
  • major clinical study
  • monogenic disorder
  • mutational analysis
  • non insulin dependent diabetes mellitus
  • penetrance
  • phenotype
  • pleckstrin homology domain
  • priority journal
  • protein expression
  • protein function
  • protein phosphorylation
  • RNA sequence
  • single nucleotide polymorphism
  • whole exome sequencing
  • African American
  • allele
  • Asian continental ancestry group
  • case control study
  • Caucasian
  • genetic predisposition
  • genetics
  • Hispanic
  • insulin resistance
  • metabolism
  • odds ratio
  • African Americans
  • Alleles
  • Asian Continental Ancestry Group
  • Case-Control Studies
  • Diabetes Mellitus, Type 2
  • European Continental Ancestry Group
  • Fasting
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Hispanic Americans
  • Humans
  • Insulin
  • Insulin Resistance
  • Odds Ratio
  • Proto-Oncogene Proteins c-akt

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Internal Medicine - Epidemiology
  • Genetic and Molecular Epidemiology
  • Diabetes - Islet Patophysiology
  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease
  • Diabetic Complications

ISBN/ISSN/Other

  • ISSN: 0012-1797