Linkage and Association Study of Neurotrophins and Their Receptors as Novel Susceptibility Genes for Childhood IgA Nephropathy

Abstract

Neurotrophins (NTs) and their receptors (NTRs) are known to be important for pathogenesis of various inflammatory diseases that occur in not only neuronal but also nonneuronal tissues, including kidney. Here, we investigated association between childhood IgA nephropathy (IgAN) and single nucleotide polymorphisms (SNPs) of genes encoding NTs [nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)] and NTRs [nerve growth factor receptor (NGFR) and neurotrophic tyrosine kinase receptor 1-3 (NTRK1-3)]. The genotyping data of 197 patients and 289 control subjects revealed significant association between NGF SNP rs11102930 and presence of IgAN. Patient subgroup analysis revealed that that the presence of nephrotic range proteinuria (Ͼ40 mg/m 2 /h) was associated with rs6334 of NTRK1 and rs11030104, rs7103411, rs7103873, and rs6484320 of BDNF. Significant genotype differences were observed in podocyte foot process effacement for rs1187321 and rs1187323 of NTRK2. Furthermore, some SNPs showed significantly different genotype distribution between patients with or without pathologically advanced disease markers, specifically in rs6334 of NTRK1. Our results suggest that SNPs of NTs and NTRs are associated with susceptibility, pathological advancement, podocyte foot process effacement, and development of proteinuria in childhood IgAN. (Pediatr Res 69: 299-305, 2011)

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

“…The first two pathways had already been well studied and validated. 26,30 In our study, we chose the latter two which have less literature support and have inconsistent results to GSEA for experimental validation. Wnt signaling was reported as a dysregulated process in CARNIVAL and is known to be involved in podocyte injury and renal fibrosis.…”

NGF (−198C > T, Ala35Val) and p75NTR (Ser205Leu) gene mutations are associated with liver function in different histopathological profiles of the patients with chronic viral hepatitis in the Brazilian Amazon

“…Considering that the variant alters NGF gene expression (Akkad et al, 2008, Hahn et al, 2011, in the context of viral liver diseases, it is proposed that negative gene maintenance be detrimental to organ tissue integrity in the most advanced aggression profiles, which underscores the importance of NGF in controlling liver damage. In fact, in experimentally intoxicated mice, it has been shown that NGF expression by hepatocytes is directly regulated in areas of tissue regeneration during aggression (Oakley et al, 2003) (which in humans is a characteristic maintained in the advanced fibrosis stage) being pointed as a potential determinant in the resolution of the fibrotic response (Amoras et al, 2015).…”

“…The -198C > T polymorphism (rs11102930) located in the promoter region of the NGF gene has been associated with multiple sclerosis (Akkad et al, 2008), childhood IgA neuropathy (Hahn et al, 2011) and asthmatic disease (Szczepankiewicz et al, 2012). These studies propose that substitution of cytosine with thymine in that specific position (nt − 198) modifies the binding site for transcription factors such as vitamin D receptor (VDR) and specificity protein 1 (Sp1), which in turn alters NGF expression.…”

“…The polymorphism + 273C > T (rs6330) is characterized by the substitution of a cytosine with a thymine at position + 273 of the exon, which causes the change in the amino acid alanine to valine (Ala35Val) at position 35 of the peptide (Cozza et al, 2008). The increase in the molar mass generated by the change in amino acids modifies the tertiary structure of the protein and leads to changes in signaling, which in multiple sclerosis represents a protective factor (Hahn et al, 2011). The T allele was also considered neuroprotective in patients with Alzheimer's disease (Nagata et al, 2011) and a predictor of efficacy of cognitive behavioral therapy in children with anxiety (Lester et al, 2012).…”

Analysis of the Expression of Neurotrophins and Their Receptors in Adult Zebrafish Kidney

“…Neurotrophins and receptors are involved in different events to ensure the correct functioning of the kidney, such as growth, differentiation, and regulation of renal tubule transport. Indeed, recent functional in vivo studies, in mice models and in vitro in human patients, have revealed a close association between neurotrophin/receptor pathways and kidney diseases [27][28][29]. However, further studies using emerging animal models [30], such as zebrafish (Danio rerio), could be useful to elucidate the specific mechanisms of these pathologies.…”