Common genetic variants in GAL, GAP43 and NRSN1 and interaction networks confer susceptibility to Hirschsprung disease

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.

Genetic variants in RET, ARHGEF3 and CTNNAL1, and relevant interaction networks, contribute to the risk of Hirschsprung disease

“…It has recently been demonstrated that the interaction between RET and PHOX2B polymorphisms substantially affects the risk of Hirschsprung disease, suggesting that HSCR, as a multifactorial genetic disorder, requires the interactions of multiple unlinked genes to produce the phenotype [20]. In a recent study, we have shown that genetic markers within GAL, GAP43 and NRSN1 contribute to the altered HSCR susceptibility, and importantly, the interaction networks among GAP43, NRSN1 and PTCH1 confer an increased risk to Hirschsprung disease [21].…”

“…We also used GeneMANIA, a flexible user-friendly database, to explore the functional association networks among RET, ARHGEF3, and CTNNAL1 and our previously studied GAL, GAP43, NRSN1, PTCH1, GABRG2 and RELN genes [21]. As shown in Figure 2C, gene function prediction indicated that RET, ARHGEF3, and CTNNAL1 might be involved in the positive regulation of neuron projection development, regulation of cell projection organization, and small GTPasemediated signal transduction.…”

“…Taking advantage of the GeneMANIA platform, we then explored functionally related gene-gene interaction networks among RET, ARHGEF3, and CTNNAL1, and our previously studied GAL, GAP43, NRSN1, PTCH1, GABRG2 and RELN genes [21]. These HSCRassociated genes were linked to each other through coexpression, genetic interactions, co-localization, or they might be involved in the same pathways or might be targeted by the same microRNAs ( Figure 2C).…”

“…Genotyping was performed using the MassARRAY iPLEX Gold system (Sequenom, San Diego, CA), and Figure 3B presents representative mass spectra of the 14 genetic variants in the RET gene. Additionally, we recruited multiple criteria for genotyping quality control, similar to previous study [21].…”

Growth‐associated protein 43 promotes thyroid cancer cell lines progression via epithelial‐mesenchymal transition

“…Consistently, it also plays a fundamental function in neural growth, axonal regeneration and stabilisation of synaptic function . A study indicated that GAP43 genetic variants and its gene network interaction may associate with the susceptibility to Hirschsprung disease . A considerable report of the mechanisms indicated that GAP43 may promote non‐small lung cancer (NSLC) cell migration by activating Rac1 and mediating F‐actin cytoskeleton polymerisation .…”