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.
Bibliographical noteFunding Information:
The authors acknowledge the following funding sources: Academy of Finland (102318, 129293, 128315, 129330, 131593, 139635, 121584, 126925, 124282, 129378, 258753, 123885, 124243); Action on Hearing Loss (G51); Jalmari and Rauha Ahokas Foundation; American Diabetes Association (7-12-MN-02); Archimedes Foundation (3.2.1001.11-0033); Atlantic Canada Opportunities Agency; Augustinus Foundation; Becket Foundation; Alfred Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; City of Kuopio and Social Insurance Institution of Finland (4/26/2010);
© 2017 by the American Diabetes Association.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism