A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Diabetes
Authors
Keywords
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.

Year of Publication
2017
Journal
Diabetes
Volume
66
Issue
7
Pages
2019-2032
Date Published
2017 Jul
ISSN
1939-327X
DOI
10.2337/db16-1329
PubMed ID
28341696
PubMed Central ID
PMC5482074
Links
Grant list
U01 DK085501 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
R01 AG042188 / AG / NIA NIH HHS / United States
K24 DK110550 / DK / NIDDK NIH HHS / United States
R01 AG046949 / AG / NIA NIH HHS / United States
U01 DK085524 / DK / NIDDK NIH HHS / United States
K12 CA139160 / CA / NCI NIH HHS / United States
U01 DK085545 / DK / NIDDK NIH HHS / United States
R01 DA006227 / DA / NIDA NIH HHS / United States
R01 MH107666 / MH / NIMH NIH HHS / United States
R01 MH101782 / MH / NIMH NIH HHS / United States
R01 DK098032 / DK / NIDDK NIH HHS / United States
R01 MH101810 / MH / NIMH NIH HHS / United States
R01 MH101819 / MH / NIMH NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 DA033684 / DA / NIDA NIH HHS / United States
HHSN268201300048C / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 MH090936 / MH / NIMH NIH HHS / United States
R01 DK062370 / DK / NIDDK NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL102830 / HL / NHLBI NIH HHS / United States
R01 DK073541 / DK / NIDDK NIH HHS / United States
HHSN268201300049C / HL / NHLBI NIH HHS / United States
R01 DK066358 / DK / NIDDK NIH HHS / United States
RC2 DK088389 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
HHSN268201300047C / HL / NHLBI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
HHSN268201300050C / HL / NHLBI NIH HHS / United States
U01 DK085584 / DK / NIDDK NIH HHS / United States
P01 AG027734 / AG / NIA NIH HHS / United States
R01 MH090951 / MH / NIMH NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
R01 MH101820 / MH / NIMH NIH HHS / United States
R01 MH101825 / MH / NIMH NIH HHS / United States
R01 MH090948 / MH / NIMH NIH HHS / United States
R01 MH090941 / MH / NIMH NIH HHS / United States
Wellcome Trust / United Kingdom
HHSN268201300046C / HL / NHLBI NIH HHS / United States
Z01 HG000024 / HG / NHGRI NIH HHS / United States
R01 MH101822 / MH / NIMH NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
R01 MH090937 / MH / NIMH NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States