Understanding the Links among neuromedin U Gene, beta2-adrenoceptor Gene and Bone Health: An Observational Study in European Children

Abstract

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.

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…A recent observational study showed that NmU polymorphisms are linked to bone density and quality in children, particularly when associated with polymorphisms in genes related to the sympathetic nervous system (121 ).…”

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

“…Although considerable data from animal models are available, suggesting multiple functions for NMU , very few studies on humans have been performed [ 10 , 13 ]. Hainerovà et al [ 10 ] identified an association between the rare homozygotes status in a missense variant of NMU gene and the adult overweight-obesity risk, with males showing increased waist and hip circumferences.…”

“…For this analysis, a subgroup of 4,678 samples was randomly selected from the total study population of European descent children, stratifying by age, sex and country (about 600 subjects from each country) [ 13 , 17 , 18 ].…”

“…For this reason, a high impact on peptide function is expected for human genetic variations. Following the haplotype approach, we have recently identified an association between variations in a NMU haplotype block and bone stiffness in a children population [ 13 ].…”

β2‑adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis

“…Three functionally relevant β2AR gene single-nucleotide polymorphisms (SNPs) (Arg16Gly, rs1042713; Gln27Glu, rs1042714; Thr164Ile, rs1800888) have been associated with joint disorder, functional gastrointestinal disorders playing an important role in vascular regulation (31)(32)(33)(34) and bronchial smooth muscle tone (35). In particular, Gln27Glu variant is associated with bone health (36), RA (37,38), functional gastrointestinal diagnoses and bowel symptoms severity (39).…”