The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes

Research output: Contribution to journalJournal articleResearchpeer-review

T Sparsø, G Andersen, T Nielsen, K S Burgdorf, Anette Marianne Prior Gjesing, A L Nielsen, Anders Albrechtsen, S S Rasmussen, Torben Jørgensen, K Borch-Johnsen, A Sandbaek, T Lauritzen, S Madsbad, T Hansen, Oluf Pedersen

AIMS/HYPOTHESIS: Recent genome-wide association studies have suggested that a polymorphism in GCKR, the gene encoding the glucokinase regulatory protein, is involved in triacylglycerol regulation. Our aim was to examine in large-scale studies the common GCKR rs780094 polymorphism in relation to metabolic traits (mainly fasting hypertriacylglycerolaemia) and traits related to pancreatic beta cell function. METHODS: The polymorphism was genotyped in 16,853 Danes using Taqman allelic discrimination. Association was analysed in case-control studies and quantitative trait analyses. We also analysed the possible interactive effect between the GCK -30G>A polymorphism and the GCKR rs780094 variant on metabolic traits. RESULTS: The minor GCKR A-allele of rs780094 is associated with an increased level of fasting serum triacylglycerol (p = 6 x 10(-14)), impaired fasting (p = 0.001) and OGTT-related insulin release (p = 3 x 10(-6)), reduced homeostasis model assessment of insulin resistance (p = 0.0004), WHO-defined dyslipidaemia (p = 6 x 10(-9)) and a modestly decreased risk of type 2 diabetes (p = 0.01). Significantly increased fasting serum insulin concentrations were demonstrated when analysing the GCK -30A and GCKR rs780094 G-alleles in an additive model. CONCLUSIONS/INTERPRETATION: The GCKR rs780094 polymorphism, or another variant with which it is in tight linkage disequilibrium, is likely to increase glucokinase regulatory protein activity to induce improved glycaemic regulation at the expense of hypertriacylglycerolaemia as reflected in the present study of 16,853 Danes. We also suggest an additive effect of GCK and GCKR risk alleles on plasma glucose and serum insulin release.
Original languageEnglish
JournalDiabetologia
Volume51
Issue number1
Pages (from-to)70-5
Number of pages5
ISSN0012-186X
DOIs
Publication statusPublished - 2007

Bibliographical note

Keywords: Adult; Diabetes Mellitus, Type 2; Female; Glucokinase; Glucose; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Receptors, Cytoplasmic and Nuclear; Risk; Triglycerides

ID: 10027035