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

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 - P L o S One

JF - P L o S One

IS - 6

ER -