title: Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B.
abstract: OBJECTIVE
  The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry.
  
  
  METHODS
  Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay.
  
  
  RESULTS
  The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples).
  
  
  CONCLUSIONS
  Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.
authors.affiliation: Department of Experimental and Clinical Medicine, Viale Europa, Campus Germaneto, 88100 Catanzaro, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: Hribal
authors.forename: I
authors.initials: I
authors.lastname: Presta
authors.forename: T
authors.initials: T
authors.lastname: Procopio
authors.forename: M A
authors.initials: MA
authors.lastname: Marini
authors.forename: A
authors.initials: A
authors.lastname: Stančáková
authors.forename: J
authors.initials: J
authors.lastname: Kuusisto
authors.forename: F
authors.initials: F
authors.lastname: Andreozzi
authors.forename: A
authors.initials: A
authors.lastname: Hammarstedt
authors.forename: P-A
authors.initials: PA
authors.lastname: Jansson
authors.forename: N
authors.initials: N
authors.lastname: Grarup
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.forename: N
authors.initials: N
authors.lastname: Stefan
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
authors.forename: H U
authors.initials: HU
authors.lastname: Häring
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: U
authors.initials: U
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Laakso
authors.forename: G
authors.initials: G
authors.lastname: Sesti
mesh_terms: D000328:Adult; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007328:Insulin