The interplay of common genetic variants NRG1 rs2439302 and RET rs2435357 increases the risk of developing Hirschsprung’s disease

Introduction: As a congenital and genetically related disease, many single nucleotide polymorphisms (SNPs) have been reported to be associated with the risk of HSCR. Our previous research showed that SNP rs2439302 (NRG1) interacted rs2435357 (RET) increase HSCR development. However, underlying molecular mechanism is still not well understood. Methods: were genotyped in 470 cases. The expression NRG1 RET was investigated colon patients. Knockdown homologs performed zebrafish investigate their synergistic effect on ENS polymorphism neuron proliferation, migration, differentiation SHSY-5Y cells IPSCs. Results: Significant downregulation noticed aganglionic segment patients GG/rs2435357 TT genotype. double mutants caused most severe reduction enteric numbers than mutant or hindgut zebrafish. IPSCs genotype exhibited decreased proliferative, differentiative capacity. CTCF considerably higher binding ability CC GG. further decrease SOX10 via PI3K/Akt pathway, which regulates by directly rs2435357. Discussion: GG increases developing affecting transcription factor interacting regulate PI3K/Akt/SOX10 pathway.