title: Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals.
abstract: OBJECTIVE
  Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting.
  
  
  METHODS
  By applying an additive genetic model, 14 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n = 6,039).
  
  
  RESULTS
  Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p = 4.0 × 10⁻⁷) and increased disposition index of 5.6% (p = 6.4 × 10⁻⁵). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p = 0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p = 0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p = 0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p = 0.00036) and 4.0% decrease in Matsuda index (p = 2 × 10⁻⁴).
  
  
  CONCLUSIONS
  Our correlative findings from analysing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1, DIKU Building, Room 1.1.N121, DK-2100 Copenhagen, Denmark. Kristoffer.Burgdorf@sund.ku.dk
authors.forename: K S
authors.initials: KS
authors.lastname: Burgdorf
authors.forename: A P
authors.initials: AP
authors.lastname: Gjesing
authors.forename: N
authors.initials: N
authors.lastname: Grarup
authors.forename: J M
authors.initials: JM
authors.lastname: Justesen
authors.forename: C H
authors.initials: CH
authors.lastname: Sandholt
authors.forename: D R
authors.initials: DR
authors.lastname: Witte
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
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: D019881:Aminoacyltransferases / Q000235:genetics*; D015992:Body Mass Index; D002353:Carrier State; D003430:Cross-Sectional Studies; D003718:Denmark; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000235:genetics; D007333:Insulin Resistance; D008245:Lysophospholipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009765:Obesity / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*; D012727:Sex Characteristics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D049629:Waist-Hip Ratio
chemical_list: C434476:LRP1B protein, human; D011973:Receptors, LDL; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D008245:Lysophospholipase; C561408:LYPLAL1 protein, human