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Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies

Journal article
Authors B. Friedrich
P. Weyrich
A. Stancakova
J. Wang
J. Kuusisto
M. Laakso
G. Sesti
E. Succurro
Ulf Smith
T. Hansen
O. Pedersen
F. Machicao
S. Schafer
F. Lang
T. Risler
S. Ullrich
N. Stefan
A. Fritsche
H. U. Haring
Published in PLoS One
Volume 3
Issue 11
Pages e3506
ISSN 1932-6203
Publication year 2008
Published at
Pages e3506
Language en
Keywords Adult, Aged, Cohort Studies, Diabetes Mellitus, Type 2/*genetics, Europe, Female, Gene Frequency, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Humans, Immediate-Early Proteins/*genetics, Insulin/*secretion, *Linkage (Genetics), Male, Metabolic Networks and Pathways/genetics, Middle Aged, *Polymorphism, Single Nucleotide/physiology, Protein-Serine-Threonine Kinases/*genetics
Subject categories Medical and Health Sciences

Abstract

HYPOTHESIS: Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans. METHODS: Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals. RESULTS: Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUC(C-Peptide)/AUC(Glc) ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMIxrs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI< or =25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC(Ins)/AUC(Glc) (TT: 226+/-7, XG: 246+/-9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71-1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers. CONCLUSIONS: The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.

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