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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

Manning, Alisa; Ladenvall, Claes LU ; Nilsson, Peter LU ; V. Varga, Tibor LU ; Franks, Paul LU ; Rosengren, Anders LU ; Melander, Olle LU ; Orho-Melander, Marju LU ; Kravic, Jasmina LU and Groop, Leif LU , et al. (2017) In Diabetes 66(7). p.2019-2032
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... (More)
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. (Less)
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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
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Diabetes
volume
66
issue
7
pages
2019 - 2032
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85021073183
ISSN
0012-1797
DOI
10.2337/db16-1329
language
English
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yes
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76c07d58-5f95-438a-b963-22cd17b5560a
date added to LUP
2019-01-22 11:12:42
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2019-08-14 04:31:06
@article{76c07d58-5f95-438a-b963-22cd17b5560a,
  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. © 2017 by the American Diabetes Association.},
  author       = {Manning, Alisa and Ladenvall, Claes and Nilsson, Peter and V. Varga, Tibor and Franks, Paul and Rosengren, Anders and Melander, Olle and Orho-Melander, Marju and Kravic, Jasmina and Groop, Leif and Lindgren, Cecilia M. and , },
  issn         = {0012-1797},
  keyword      = {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},
  language     = {eng},
  number       = {7},
  pages        = {2019--2032},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {A low-frequency inactivating AKT2 variant enriched in the finnish population is associated with fasting insulin levels and type 2 diabetes risk},
  url          = {http://dx.doi.org/10.2337/db16-1329},
  volume       = {66},
  year         = {2017},
}