• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)