title: Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents.
abstract: BACKGROUND
  The global prevalence of obesity and overweight is increasing rapidly among adults as well as among children and adolescents. Recent genome-wide association studies have provided strong support for association between variants in the FTO gene and obesity. We sequenced regions of the FTO gene to identify novel variants that are associated with obesity and related metabolic traits.
  
  
  RESULTS
  We screened exons 3 and 4 including exon-intron boundaries in FTO in 48 obese children and adolescents and identified three novel single nucleotide polymorphism in the fourth intronic region, (c.896+37A>G, c.896+117C>G and c.896+223A>G). We further genotyped c.896+223A>G in 962 subjects, 450 well-characterized obese children and adolescents and 512 adolescents with normal weight. Evidence for differences in genotype frequencies were not detected for the c.896+223A>G variant between extremely obese children and adolescents and normal weight adolescents (P=0.406, OR=1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P=0.017) and increased degree of insulin resistance (P=0.025). There were in addition no differences in body mass index (BMI) or BMI standard deviation score (SDS) levels among the obese subjects according to genotype and the associations with insulin levels and insulin resistance remained significant when adjusting for BMI SDS.
  
  
  CONCLUSIONS
  These findings suggest that this novel variant in FTO is affecting metabolic phenotypes such as insulin resistance, which are not mediated through differences in BMI levels.
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: J A
authors.initials: JA
authors.lastname: Jacobsson
authors.forename: J
authors.initials: J
authors.lastname: Klovins
authors.forename: I
authors.initials: I
authors.lastname: Kapa
authors.forename: P
authors.initials: P
authors.lastname: Danielsson
authors.forename: V
authors.initials: V
authors.lastname: Svensson
authors.forename: M
authors.initials: M
authors.lastname: Ridderstråle
authors.forename: U
authors.initials: U
authors.lastname: Gyllensten
authors.forename: C
authors.initials: C
authors.lastname: Marcus
authors.forename: R
authors.initials: R
authors.lastname: Fredriksson
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D000293:Adolescent; D001786:Blood Glucose / Q000235:genetics*; D015992:Body Mass Index; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: D001786:Blood Glucose