title: The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes.
abstract: OBJECTIVE
  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
  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 [corrected] serum insulin release.
authors.affiliation: Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13, DK-2820, Gentofte, Denmark. tspr@steno.dk
authors.forename: T
authors.initials: T
authors.lastname: Sparsø
authors.forename: G
authors.initials: G
authors.lastname: Andersen
authors.forename: T
authors.initials: T
authors.lastname: Nielsen
authors.forename: K S
authors.initials: KS
authors.lastname: Burgdorf
authors.forename: A P
authors.initials: AP
authors.lastname: Gjesing
authors.forename: A L
authors.initials: AL
authors.lastname: Nielsen
authors.forename: A
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: S S
authors.initials: SS
authors.lastname: Rasmussen
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
authors.forename: K
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: A
authors.initials: A
authors.lastname: Sandbaek
authors.forename: T
authors.initials: T
authors.lastname: Lauritzen
authors.forename: S
authors.initials: S
authors.lastname: Madsbad
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology*; D012306:Risk; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
chemical_list: D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; C105556:glucokinase receptor; D005941:Glucokinase; D005947:Glucose