A low-frequency inactivating AKT2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 diabetes risk

2.50
Hdl Handle:
http://hdl.handle.net/11287/620413
Title:
A low-frequency inactivating AKT2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 diabetes risk
Authors:
Manning, A [et al]; Hattersley, Andrew T.
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.
Citation:
A low-frequency inactivating AKT2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 diabetes risk. Diabetes. 2017: 66(7) 2019-2032
Publisher:
American Diabetes Association
Journal:
Diabetes
Issue Date:
Jul-2017
URI:
http://hdl.handle.net/11287/620413
DOI:
10.2337/db16-1329
PubMed ID:
28341696
Additional Links:
http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=28341696
Type:
Journal Article
Language:
en
Appears in Collections:
Diabetes/Endocrine Services; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorManning, A [et al]en
dc.contributor.authorHattersley, Andrew T.en
dc.date.accessioned2017-10-04T11:54:25Z-
dc.date.available2017-10-04T11:54:25Z-
dc.date.issued2017-07-
dc.identifier.citationA low-frequency inactivating AKT2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 diabetes risk. Diabetes. 2017: 66(7) 2019-2032en
dc.identifier.pmid28341696-
dc.identifier.doi10.2337/db16-1329-
dc.identifier.urihttp://hdl.handle.net/11287/620413-
dc.description.abstractTo 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.en
dc.language.isoenen
dc.publisherAmerican Diabetes Associationen
dc.relation.urlhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=28341696en
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleA low-frequency inactivating AKT2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 diabetes risken
dc.typeJournal Articleen
dc.identifier.journalDiabetesen
dc.type.versionPublisheden

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