BDNF and NGF gene polymorphisms and urine BDNF–NGF levels in children with primary monosymptomatic nocturnal enuresis

Abstract

The pathophysiology and genetic influences in nocturnal enuresis have not been fully elucidated. Delayed neuronal maturation has been suggested as a pathogenetic mechanism in primary monosymptomatic nocturnal enuresis (PMNE). Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins affecting maturation of the nervous system. The aim of this preliminary study was to investigate BDNF and NGF gene polymorphisms and urine levels of BDNF and NGF in children with PMNE as a first time. The single-nucleotide polymorphisms of BDNF (rs6265:G>A:Val66Met; rs8192466:C>T:Thr2Ile) and NGF (rs6330:C>T:Ala35Val, rs11466112:C>T:Arg221Trp) were investigated by comparing 104 children with PMNE and 140 healthy control subjects. Children with non-PMNE were excluded. DNA isolation and detection of polymorphisms were performed by real-time polymerase chain reaction. In addition, urine BDNF and NGF levels of 47 PMNE and 29 healthy children were measured by enzyme-linked immunosorbent assay method and normalized to urine creatinine (Cr) concentration for comparisons. There were no differences in genotype and allele frequencies of BDNF rs6265 and NGF rs6330 polymorphisms between patients with PMNE and the control group (P>0.05). No mutant alleles were found in BDNF rs8192466 and NGF rs11466112 polymorphisms in either group. Children with PMNE had higher urine BDNF/Cr (0.020±0.010 vs 0.010±0.002; P=0.008) and NGF/Cr ratio (3.01±1.87 pg/mg vs 1.77±0.26 pg/mg; P=0.002) compared with the control subjects. However, no significant differences were found in BDNF/Cr and NGF/Cr values between GG, GA, and AA genotypes of BDNF rs6265 polymorphismand CC and CT genotypes of NGF rs6330 polymorphism (P>0.05). In this study, no association of BDNF and NGF gene polymorphisms with PMNE was found, and urine neurotrophin concentrations were not directly influenced by investigated polymorphisms. Although, previously increased urine neurotrophin secretion has been found in detrusor overactivity, bladder inflammation, and dysfunctional voiding, this preliminary results also showed an increase in neurotrophins in PMNE.Higher urine neurotrophin levels may be related to delayed and continued neuronal maturation or increased production of neurotrophins in the bladder. The increased urine neurotrophins in PMNE may be an indicator of increased sensory nerve excitability of the bladder, contributing to the development of enuresis. This study showed that investigated neurotrophin gene polymorphisms did not make a significant contribution to the development of PMNE, but urine levels of neurotrophin gene products were higher in PMNE. Owing to the complexity and heterogeneity of genotype-phenotype relationships in enuresis, further studies are needed in PMNE.