title: Implications of central obesity-related variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on quantitative metabolic traits in adult Danes.
abstract: BACKGROUND
  Two meta-analyses of genome-wide association studies (GWAS) have suggested that four variants: rs2605100 in lysophospholipase-like 1 (LYPLAL1), rs10146997 in neuroxin 3 (NRXN3), rs545854 in methionine sulfoxide reductase A (MSRA), and rs987237 in transcription factor activating enhancer-binding protein 2 beta (TFAP2B) associate with measures of central obesity. To elucidate potential underlying phenotypes we aimed to investigate whether these variants associated with: 1) quantitative metabolic traits, 2) anthropometric measures (waist circumference (WC), waist-hip ratio, and BMI), or 3) type 2 diabetes, and central and general overweight and obesity.
  
  
  RESULTS
  The four variants were genotyped in Danish individuals using KASPar®. Quantitative metabolic traits were examined in a population-based sample (n = 6,038) and WC and BMI were furthermore analyzed in a combined study sample (n = 13,507). Case-control studies of diabetes and adiposity included 15,326 individuals. The major G-allele of LYPLAL1 rs2605100 associated with increased fasting serum triglyceride concentrations (per allele effect (β) = 3%(1;5(95%CI)), p(additive) = 2.7×10(-3)), an association driven by the male gender (p(interaction) = 0.02). The same allele associated with increased fasting serum insulin concentrations (β = 3%(1;5), p(additive) = 2.5×10(-3)) and increased insulin resistance (HOMA-IR) (β = 4%(1;6), p(additive) = 1.5×10(-3)). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (β = 0.55cm (0.20;0.89), p(additive) = 1.7×10(-3), p(interaction) = 1.0×10(-3)), but showed no associations with obesity related metabolic traits. The MSRA rs545854 and TFAP2B rs987237 showed nominal associations with central obesity; however, no underlying metabolic phenotypes became obvious, when investigating quantitative metabolic traits. None of the variants influenced the prevalence of type 2 diabetes.
  
  
  CONCLUSIONS
  We demonstrate that several of the central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B associate with metabolic and anthropometric traits in Danish adults. However, analyses were made without adjusting for multiple testing, and further studies are needed to confirm the putative role of LYPLAL1, NRXN3, MSRA, and TFAP2B in the pathophysiology of obesity.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Dorthe S
authors.initials: DS
authors.lastname: Bille
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Justesen
authors.forename: Camilla H
authors.initials: CH
authors.lastname: Sandholt
authors.forename: Annelli
authors.initials: A
authors.lastname: Sandbæk
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Jens-Christian
authors.initials: JC
authors.lastname: Holm
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D050154:Adiposity / Q000235:genetics; D000328:Adult; D016022:Case-Control Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008245:Lysophospholipase / Q000235:genetics*; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D012727:Sex Characteristics; D050656:Transcription Factor AP-2 / Q000235:genetics*; D055105:Waist Circumference / Q000235:genetics; D049629:Waist-Hip Ratio; D044465:White People / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D050656:Transcription Factor AP-2; C082354:neurexin IIIalpha; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D008245:Lysophospholipase; C561408:LYPLAL1 protein, human