TY - JOUR
T1 - Implications of central obesity-related variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on quantitative metabolic traits in adult Danes
AU - Bille, Dorthe S
AU - Banasik, Karina
AU - Justesen, Johanne M
AU - Sandholt, Camilla H
AU - Sandbæk, Annelli
AU - Lauritzen, Torsten
AU - Jørgensen, Torben
AU - Witte, Daniel R
AU - Holm, Jens-Christian
AU - Hansen, Torben
AU - Pedersen, Oluf
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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. 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 (β) = 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 (β = 3%(1;5), padditive = 2.5×10-3) and increased insulin resistance (HOMA-IR) (β = 4%(1;6), padditive = 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), 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. Conclusion/Significance: 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.
AB - 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. 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 (β) = 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 (β = 3%(1;5), padditive = 2.5×10-3) and increased insulin resistance (HOMA-IR) (β = 4%(1;6), padditive = 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), 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. Conclusion/Significance: 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.
KW - Adiposity
KW - Adult
KW - Case-Control Studies
KW - Denmark
KW - Diabetes Mellitus, Type 2
KW - European Continental Ancestry Group
KW - Female
KW - Genetic Variation
KW - Genome-Wide Association Study
KW - Humans
KW - Lysophospholipase
KW - Male
KW - Methionine Sulfoxide Reductases
KW - Middle Aged
KW - Nerve Tissue Proteins
KW - Obesity
KW - Sex Characteristics
KW - Transcription Factor AP-2
KW - Waist Circumference
KW - Waist-Hip Ratio
U2 - 10.1371/journal.pone.0020640
DO - 10.1371/journal.pone.0020640
M3 - Journal article
C2 - 21674055
SN - 1932-6203
VL - 6
SP - e20640
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 6
ER -
