Implications of central obesity-related variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on quantitative metabolic traits in adult Danes

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Dorthe S Bille, Karina Banasik, Johanne M Justesen, Camilla H Sandholt, Annelli Sandbæk, Torsten Lauritzen, Torben Jørgensen, Daniel R Witte, Jens-Christian Holm, Torben Hansen, Oluf Pedersen

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.

Methodology/Principal Findings
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 (ß) = 3%(1;5(95%CI)), padditive = 2.7×10-3), an association driven by the male gender (pinteraction = 0.02). The same allele associated with increased fasting serum insulin concentrations (ß = 3%(1;5), padditive = 2.5×10-3) and increased insulin resistance (HOMA-IR) (ß = 4%(1;6), padditive = 1.5×10-3). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (ß = 0.55cm (0.20;0.89), padditive = 1.7×10-3, pinteraction = 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.

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.

Original languageEnglish
JournalP L o S One
Issue number6
Pages (from-to)e20640
Number of pages7
Publication statusPublished - 1 Jun 2011

    Research areas

  • Adiposity, Adult, Case-Control Studies, Denmark, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genetic Variation, Genome-Wide Association Study, Humans, Lysophospholipase, Male, Methionine Sulfoxide Reductases, Middle Aged, Nerve Tissue Proteins, Obesity, Sex Characteristics, Transcription Factor AP-2, Waist Circumference, Waist-Hip Ratio

ID: 35314525