Understanding the links among neuromedin U gene, beta2-adrenoceptor gene and bone health: an observational study in European children.
Neuromedin U, encoded by the NMU gene, is a hypothalamic neuropeptide that regulates both energy metabolism and bone mass. The beta-2 adrenergic receptor, encoded by the ADRB2 gene, mediates several effects of catecholamine hormones and neurotransmitters in bone. We investigated whether NMU single nucleotide polymorphisms (SNPs) and haplotypes, as well as functional ADRB2 SNPs, are associated with bone stiffness in children from the IDEFICS cohort, also evaluating whether NMU and ADRB2 interact to affect this trait. A sample of 2,274 subjects (52.5% boys, age 6.2 ± 1.8 years) from eight European countries, having data on calcaneus bone stiffness index (SI, mean of both feet) and genotyping (NMU gene: rs6827359, rs12500837, rs9999653; ADRB2 gene: rs1042713, rs1042714), was studied. After false discovery rate adjustment, SI was significantly associated with all NMU SNPs. rs6827359 CC homozygotes showed the strongest association (recessive model, Δ= -1.8, p=0.006). Among the five retrieved haplotypes with frequencies higher than 1% (range 2.0-43.9%), the CCT haplotype (frequency=39.7%) was associated with lower SI values (dominant model, Δ= -1.0, p=0.04) as compared to the most prevalent haplotype. A non-significant decrease in SI was observed in in ADRB2 rs1042713 GG homozygotes, while subjects carrying SI-lowering genotypes at both SNPs (frequency = 8.4%) showed much lower SI than non-carriers (Δ= -3.9, p<0.0001; p for interaction=0.025). The association was more evident in preschool girls, in whom SI showed a curvilinear trend across ages. In subgroup analyses, rs9999653 CC NMU or both GG ADRB2 genotypes were associated with either lower serum calcium or β-CrossLaps levels (p=0.01). This study in European children shows, for the first time in humans, a role for NMU gene through interaction with ADRB2 gene in bone strength regulation, more evident in preschool girls.
Research Laboratories, Fondazione di Ricerca e Cura "Giovanni Paolo II", Università Cattolica del Sacro Cuore, Campobasso, Italy.
Francesco
F
Gianfagna
Daniela
D
Cugino
Wolfgang
W
Ahrens
Mark E S
ME
Bailey
Karin
K
Bammann
Diana
D
Herrmann
Anna C
AC
Koni
Yiannis
Y
Kourides
Staffan
S
Marild
Dénes
D
Molnár
Luis A
LA
Moreno
Yannis P
YP
Pitsiladis
Paola
P
Russo
Alfonso
A
Siani
Sabina
S
Sieri
Isabelle
I
Sioen
Toomas
T
Veidebaum
Licia
L
Iacoviello
D000483:Alleles; D001696:Biomechanical Phenomena; D001847:Bone Diseases / Q000235:genetics / Q000503:physiopathology; D001842:Bone and Bones / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D004843:Epistasis, Genetic; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D006262:Health; D006801:Humans; D008297:Male; D009479:Neuropeptides / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012727:Sex Characteristics
D009479:Neuropeptides; D018343:Receptors, Adrenergic, beta-2; C056900:neuromedin U