Abstract
Hirschsprung disease (HSCR) is a severe multifactorial genetic disorder. Microarray studies indicated GAL,GAP43 and NRSN1 might contribute to the altered risk in HSCR. Thus, we focused on genetic variations in GAL,GAP43 and NRSN1, and the gene‐gene interactions involved in HSCR susceptibility. We recruited a strategy combining case‐control study and MassArray system with interaction network analysis. For GAL,GAP43 and NRSN1, a total of 18 polymorphisms were assessed in 104 subjects with sporadic HSCR and 151 controls of Han Chinese origin. We found statistically significant differences between HSCR and control groups at 5 genetic variants. For each gene, the haplotypes combining all polymorphisms were the most significant. Based on SNPsyn, MDR and GeneMANIA analyses, we observed significant gene‐gene interactions among GAL,GAP43,NRSN1 and our previous identified RELN,GABRG2 and PTCH1. Our study for the first time indicates that genetic variants within GAL,GAP43 and NRSN1 and related gene‐gene interaction networks might be involved in the altered susceptibility to HSCR in the Han Chinese population, which might shed more light on HSCR pathogenesis.
Highlights
Hirschsprung disease (HSCR) is a complex genetic disorder caused by congenital defect of the enteric nervous system (ENS) which is derived from neural crest cells (NCCs)
It has been demonstrated that reelin blockade results in decreased levels of phospho-GAP43 in the superior colliculus, suggesting the interaction of reelin signalling and phospho-GAP43 might be involved in the development of neural circuits.[20]. With all these lines of evidence and results, we aimed to explore whether genetic variants within GAL, GAP43 and Neurensin 1 (NRSN1) might contribute to the altered susceptibility to HSCR, and based on the 18 polymorphisms involved in this study (Figure 1A), we further assessed the interaction relationship among GAL, GAP43, NRSN1 and our previous identified GABRG2, RELN and PTCH1 genes
We found the significance in allele distributions of the 5 positive SNPs and in genotype distributions of the 1 GAL SNP and 2 GAP43 SNPs remained after the Bonferroni correction
Summary
Hirschsprung disease (HSCR) is a complex genetic disorder caused by congenital defect of the enteric nervous system (ENS) which is derived from neural crest cells (NCCs). Cases) in which the aganglionic segment does not extend beyond the upper sigmoid, long segment HSCR (L-HSCR, 15% of cases) and total colonic aganglionosis (TCA, 5% of cases).[2] Importantly, HSCR shows a dramatic sex bias with at least 4 times more males affected than females in S-HSCR (male:female % 1:1 in L-HSCR) for causes that remain unclear.[3]. Genetic factors or multiple gene interactions are crucial to the development of Hirschsprung disease as HSCR is a non-Mendelian disorder in nature with low sex-dependent penetrance and interfamilial variation.[4] It has been suggested that there are variations in penetrance and severity of aganglionosis between family members
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