Dataset Information

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

ABSTRACT: 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.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 (?)?=?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 (??=?3%(1;5), p(additive)?=?2.5×10(-3)) and increased insulin resistance (HOMA-IR) (??=?4%(1;6), p(additive)?=?1.5×10(-3)). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (??=?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.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.

SUBMITTER: Bille DS

PROVIDER: S-EPMC3107232 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Bille Dorthe S DS Banasik Karina K Justesen Johanne M JM Sandholt Camilla H CH Sandbæk Annelli A Lauritzen Torsten T Jørgensen Torben T Witte Daniel R DR Holm Jens-Christian JC Hansen Torben T Pedersen Oluf O

PloS one 20110602 6

<h4>Background</h4>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) quant ...[more]

PMID: 21674055

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Project description:A genome-wide scan in unrelated US Caucasians identified rs7001819 upstream of farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and multiple variants within catenin (cadherin-associated protein), beta-like 1 (CTNNBL1) to associate strongly with body mass index (BMI). The most significantly associating variants within CTNNBL1 including rs6013029 and rs6020846 were additionally confirmed to associate with morbid obesity in a French Caucasian case-control sample. The aim of this study was to investigate the impact of these three variants on obesity, through analyses of obesity-related quantitative traits, and case-control studies in large study samples of Danes.The FDFT1 rs7001819, CTNNBL1 rs6013029 and rs6020846 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising 18,014 participants ascertained from; the population-based Inter99 cohort (n = 6,514), the ADDITION Denmark screening study cohort (n = 8,662), and a population-based sample (n = 680) and a type 2 diabetic patients group (n = 2,158) from Steno Diabetes Center.Both CTNNBL1 variants associated with body weight and height with per allele effect sizes of 1.0 [0.3-0.8] kg and 0.6 [0.2-0.9] cm, respectively, for the rs6020846 G-allele. No association was observed with BMI and waist circumference. In case-control studies neither of the CTNNBL1 variants showed association with overweight, obesity or morbid obesity (rs6013029: Odds Ratio (OR)(overweight) = 1.02 [0.90-1.16], OR(obesity) = 1.09 [0.95-1.25], OR(morbidobesity) = 1.26 [0.91-1.74]; rs6020846: OR(overweight) = 1.05 [0.93-1.18], OR(obesity) = 1.13 [1.00-1.28], OR(morbidobesity) = 1.17 [0.86-1.61]). However, in meta-analyses of the present and the previous study, both the rs6013029 T-allele and the rs6020846 G-allele increased the risk of developing morbid obesity (rs6013029: OR(combined) = 1.36 [1.12-1.64], p = 0.002; rs6020846: OR(combined) = 1.26 [1.06-1.51], p = 0.01), and obesity (rs6013029: OR(combined) = 1.17 [1.04-1.31], p = 0.007; rs6020846: OR(combined) = 1.17 [1.05-1.30], p = 0.004). The FDFT1 rs7001819 C-allele showed no association with obesity-related quantitative measures or dichotomous measures of overweight, obesity and morbid obesity.CTNNBL1 variants associated with body weight and height, and confer the risk of developing obesity in meta-analyses combining the present and a previous study. FDFT1 rs7001819 showed no association with obesity, neither when analysing quantitative traits nor when performing case-control studies of obesity.

Project description:Background & aimsWeight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy.MethodsIn a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations betwecen a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof of concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients to validate associations between quantitative traits and response to weight-loss therapy.ResultsIn the prospective study, obesity was associated with fasting gastric volume (P = .03), accelerated gastric emptying (P < .001 for solids and P = .011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P = .003), and higher postprandial levels of glucagon-like peptide 1 (P < .001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n = 509; P = .038) and satiety with abnormal waist circumference (n = 271; P = .016). Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed gastric emptying, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test.ConclusionsQuantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof of concept clinical trial, predicted response to pharmacotherapy for obesity. ClinicalTrials.gov Number: NCT01834404.

Dataset Information

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

Publications

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

Similar Datasets

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