title: The frequent UCP2 -866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes.
abstract: BACKGROUND
  Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in β-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus.
  
  
  OBJECTIVE
  To determine the influence of a functional UCP2 promoter polymorphism (-866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes.
  
  
  METHODS
  We genotyped UCP2 rs659366 in a total of 17 636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations.
  
  
  RESULTS
  We found no consistent associations between the UCP2 -866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12 984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826-0.968) P=0.00562, and AA vs GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15 107 individuals showed no association. The -866G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects (n=377) was decreased in carriers of the GG genotype (P=0.05).
  
  
  CONCLUSIONS
  The UCP2 -866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.
authors.affiliation: Hagedorn Research Institute, Gentofte, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Andersen
authors.forename: L T
authors.initials: LT
authors.lastname: Dalgaard
authors.forename: J M
authors.initials: JM
authors.lastname: Justesen
authors.forename: S
authors.initials: S
authors.lastname: Anthonsen
authors.forename: T
authors.initials: T
authors.lastname: Nielsen
authors.forename: L W
authors.initials: LW
authors.lastname: Thørner
authors.forename: D
authors.initials: D
authors.lastname: Witte
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
authors.forename: J O
authors.initials: JO
authors.lastname: Clausen
authors.forename: T
authors.initials: T
authors.lastname: Lauritzen
authors.forename: J
authors.initials: J
authors.lastname: Holmkvist
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007473:Ion Channels / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000097:blood* / Q000235:genetics; D009765:Obesity / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000071246:Uncoupling Protein 2; D044465:White People / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2