title: Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.
abstract: OBJECTIVE
  Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans.
  
  
  METHODS
  A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS).
  
  
  RESULTS
  After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all).
  
  
  CONCLUSIONS
  In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Böhm
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Ordelheide
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Caroline
authors.initials: C
authors.lastname: Ketterer
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000328:Adult; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics*; D009765:Obesity / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D015843:Serpins / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D020738:Leptin; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor