The single nucleotide polymorphisms in Smad-interacting protein 1 gene contribute to its ectopic expression and susceptibility in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is the third most common congenital disorder of the gastrointestinal tract. It is an anomalous enteric nervous system (ENS) characterized by the absence of ganglion cells in the myenteric and submucosal plexuses. It has been reported that the Smad-interacting protein 1(SIP1) is critical in embryonic development of ENS for its regulation on neural crest cells. In the present study, we analyzed 3 polymorphisms of the SIP1 gene rs41292293 (exon5), rs34961586 (exon6) and rs13017697 (exon8) to determine their potential contributions to the susceptibility of HSCR. Allele frequencies and genotype distributions were analyzed by sequence analysis in 107 HSCR patients and 107 normal controls. The SIP1 expression was carried out by using real-time PCR, western blot and immunohistochemistry. Polymorphic analysis indicated that the genotype distributions and allele frequencies in SIP1 gene rs41292293, rs34961586 and rs13017697 were statistically different between HSCR and normal controls. The expression analysis revealed that SIP1 was ectopically expressed in the aganglionic segments; neither the mRNA nor the protein levels demonstrated that the difference compared with those was in the normal segments. In conclusion, the single nucleotide polymorphisms in SIP1 gene rs41292293, rs34961586 and rs13017697 are associated with the ectopic expression of this gene in human HSCR and contribute to the susceptibility of this disease in population.