title: The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort.
abstract: OBJECTIVE
  Neuromedin U (NMU) is a hypothalamic neuropeptide with important roles in several metabolic processes, recently suggested as potential therapeutic target for obesity. We analysed the associations between NMU gene variants and haplotypes and body mass index (BMI) in a large sample of European children.
  
  
  RESULTS
  From a large European multi-center study on childhood obesity, 4,528 children (2.0-9.9 years, mean age 6.0±1.8 SD; boys 52.2%) were randomly selected, stratifying by age, sex and country, and genotyped for tag single nucleotide polymorphisms (SNPs; rs6827359, T:C; rs12500837, T:C; rs9999653,C:T) of NMU gene, then haplotypes were inferred. Regression models were applied to estimate the associations between SNPs or haplotypes and BMI as well as other anthropometric measures. BMI was associated with all NMU SNPs (p<0.05). Among five haplotypes inferred, the haplotype carrying the minor alleles (CCT, frequency = 22.3%) was the only associated with lower BMI values (beta = -0.16, 95%CI:-0.28,-0.04, p = 0.006; z-score, beta = -0.08, 95%CI:-0.14,-0.01, p = 0.019) and decreased risk of overweight/obesity (OR = 0.81, 95%CI:0.68,0.97, p = 0.020) when compared to the most prevalent haplotype (codominant model). Similar significant associations were also observed using the same variables collected after two years' time (BMI, beta = -0.25, 95%CI:-0.41,-0.08, p = 0.004; z-score, beta = -0.10, 95%CI:-0.18,-0.03, p = 0.009; overweight/obesity OR = 0.81, 95%CI:0.66,0.99, p = 0.036). The association was age-dependent in girls (interaction between CCT haplotypes and age, p = 0.008), more evident between 7 and 9 years of age. The CCT haplotype was consistently associated with lower levels of fat mass, skinfold thickness, hip and arm circumferences both at T0 and at T1, after adjustment for multiple testing (FDR-adjusted p<0.05).
  
  
  CONCLUSIONS
  This study shows an association between a NMU haplotype and anthropometric indices, mainly linked to fat mass, which appears to be age- and sex-specific in children. Genetic variations within or in linkage with this haplotype should be investigated to identify functional variants responsible for the observed phenotypic variation.
authors.affiliation: Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Isernia, Italy.|EPIMED Research Center, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: Francesco
authors.identifier: http://orcid.org/0000-0003-4615-0816
authors.initials: F
authors.lastname: Gianfagna
authors.affiliation: Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Grippi
authors.affiliation: Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany.|Faculty of Mathematics and Computer Science, Institute of Statistics, Bremen University, Bremen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Ahrens
authors.affiliation: School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Mark E S
authors.initials: ME
authors.lastname: Bailey
authors.affiliation: Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Börnhorst
authors.affiliation: Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: De Henauw
authors.affiliation: Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Foraita
authors.affiliation: School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Koni
authors.affiliation: Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Krogh
authors.affiliation: Dept. of Paediatrics, Inst. of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Mårild
authors.affiliation: Department of Paediatrics, Medical Faculty, University of Pécs, Pécs, Hungary.
authors.forename: Dénes
authors.initials: D
authors.lastname: Molnár
authors.affiliation: GENUD (Growth, Exercise, Nutrition and Development) Research Group, University of Zaragoza, Zaragoza, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Centre for Sport and Exercise Science and Medicine, University of Brighton, Brighton, United Kingdom.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Pitsiladis
authors.affiliation: Unit of Epidemiology & Population Genetics, Institute of Food Sciences, CNR, Avellino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Russo
authors.affiliation: Unit of Epidemiology & Population Genetics, Institute of Food Sciences, CNR, Avellino, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Siani
authors.affiliation: Research & Education Institute of Child Health, Strovolos, Cyprus.
authors.forename: Michael
authors.initials: M
authors.lastname: Tornaritis
authors.affiliation: Department of Chronic Diseases, National Institute for Health Development, Tallinn, Estonia.
authors.forename: Toomas
authors.initials: T
authors.lastname: Veidebaum
authors.affiliation: Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Iacoviello
mesh_terms: D000273:Adipose Tissue; D000367:Age Factors; D000483:Alleles; D000886:Anthropometry; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005060:Europe; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009479:Neuropeptides / Q000235:genetics*; D009765:Obesity / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D012885:Skinfold Thickness; D055105:Waist Circumference
chemical_list: D009479:Neuropeptides; C056900:neuromedin U