The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort

PLoS One. 2017 Feb 24;12(2):e0172698. doi: 10.1371/journal.pone.0172698. eCollection 2017.

Abstract

Background and aims: 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.

Methods and 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.

Publication types

  • Multicenter Study

MeSH terms

  • Adipose Tissue
  • Age Factors
  • Alleles
  • Anthropometry
  • Body Mass Index
  • Child
  • Child, Preschool
  • Cohort Studies
  • Europe
  • Female
  • Gene Expression
  • Gene Frequency
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Haplotypes*
  • Humans
  • Male
  • Models, Genetic
  • Neuropeptides / genetics*
  • Obesity / diagnosis
  • Obesity / genetics*
  • Obesity / physiopathology
  • Polymorphism, Single Nucleotide*
  • Sex Factors
  • Skinfold Thickness
  • Waist Circumference

Substances

  • Neuropeptides
  • neuromedin U

Grant support

This study was supported by the European Community within the Sixth RTD Framework Programme Contract no. 016181 - FOOD (WA) and by the grant from EU for the IDEFICS study. This analysis was partially supported by the Fondazione Umberto Veronesi, 2014 Young Investigator Research Programme award (FG) and the Italian Ministry of Health 2011, Young Investigator Grant n. 167/GR-2011-02351736 (FG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.