Abstract
BackgroundTwo 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 FindingsThe 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.Conclusion/SignificanceWe 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.
Highlights
Obesity is a major health problem with increasing prevalence in Western societies, and obesity, as well as the often associated insulin resistance (IR), are important risk factors for type 2 diabetes, cardiovascular diseases, hypertension, and several other chronic diseases
In the Inter99 population, the major G-allele of rs2605100 in LYPLAL1 associated with fasting serum triglyceride concentrations (per allele effect(b) = 3%, ((95% confidence interval(CI))1;5), padditive = 2.761023), fasting serum insulin concentrations (b = 3% (1;5), padd = 2.561023), and homeostasis model assessment-insulin resistance (HOMA-IR) (b = 4% (1;6), padd = 1.561023)
In the case-control study the variant associated with central obesity, measured by WC (Odds Ratio(OR)add = 0.92 (0.86–0.98(95% CI)), padd = 0.01), and the association strengthened, when WC was adjusted for BMI (Table S3)
Summary
Obesity is a major health problem with increasing prevalence in Western societies, and obesity, as well as the often associated insulin resistance (IR), are important risk factors for type 2 diabetes, cardiovascular diseases, hypertension, and several other chronic diseases. Two meta-analyses demonstrated four loci to associate with measures of central adiposity (waist circumference (WC) and waist–hip-ratio (WHR)): 1) a meta-analysis of 16 GWAS (n = 38,580) with follow-up studies in a maximum of 118,691 individuals of European origin, identified variants near lysophospholipase-like 1 (LYPLAL1), methionine sulfoxide reductase A (MSRA), and transcription factor activating enhancer-binding protein 2 beta (TFAP2B), to strongly associate with measures of central adiposity using information about adult WC and WHR [8], and 2) a large-scale meta-analysis of GWAS from the CHARGE Consortium involving 70,014 Caucasian individuals identified neuroxin 3 (NRXN3) as a novel locus for central adiposity [9]. 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
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