Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of neural crest cells in parts of the intestine. This study aims to investigate the association of vesicle-associated membrane protein 5 (VAMP5) and mutated in colorectal cancer (MCC) genetic polymorphisms and their correlated risks with HSCR. We examined the association in four polymorphisms (rs10206961, rs1254900 and rs14242 in VAMP5, rs11241200 in MCC) and HSCR susceptibility in a Southern Chinese population composed of 1473 cases and 1469 controls. Two variants in VAMP5 were replicated as associated with HSCR. Interestingly, we clarified SNPs rs10206961 and rs1254900 in VAMP5 are more essential for patients with long-segment aganglionosis (LHSCR). Relatively high expression correlation was observed between VAMP5 and MCC using data from public database showing there may exist potential genetic interactions. SNP interaction was cross-examined by logistic regression and multifactor dimensionality reduction analysis revealing that VAMP5 rs1254900 and MCC rs11241200 were interacting significantly, thereby contributing to the risk of HSCR. The results suggest that significant associations of the rs10206961 and rs14242 in VAMP5 with an increased risk of HSCR in Southern Chinese, especially in LHSCR patients. This study provided new evidence of epistatic association of VAMP5 and MCC with increased risk of HSCR.

Hirschsprung disease (HSCR) is a heterogeneous congenital disorder that affects the enteric nervous system, while neuroblastoma is an embryonal tumor of the sympathetic nervous system. Familial cases of both HSCR and neuroblastoma appear to be functionally linked to PHOX2B , which plays a key role in the development of neural crest derivatives. However, the association between common PHOX2B variants and disease risk is contested. Additionally, large-scale examination for pleiotropy or shared genetic susceptibility in sporadic HSCR and neuroblastoma cases lacks theoretical support. Here, we report the first examination of PHOX2B in 1470 HSCR and 469 neuroblastoma patients with matched healthy controls. The PHOX2B rs28647582 polymorphism was found to be associated with HSCR (P = 2.21E-03, OR = 1.26), and each subtype of the ailment (3.22E-03 ≤ P ≤ 0.43, 1.11 ≤ OR ≤ 2.32). The association between rs28647582 and NB risk was consistent with HSCR in a recessive model, though the P value was marginal (P = 0.06). These new genetic findings indicate the potential pleiotropic effects of PHOX2B in both HSCR and neuroblastoma, which could guide the development of therapeutic targets for the treatment of related neurodevelopmental disorders.

Biliary atresia (BA) is a multifactorial pathogenic disease with possible genetic components. As a member of membrane skeletal proteins in the liver and bile ducts, a haplotype composed by five single nucleotide polymorphisms (SNPs) on adducin 3 (ADD3) has been identified as associated with BA. However, limited study was designed to further elaborate the mutual relationship amongst those replicated SNPs to disease. We selected three susceptibility SNPs in ADD3 and conducted a replication study using 510 BA cases and 1473 controls to evaluate the individual function of the SNPs and further stratified the potential roles with disease and its subclinical features. Two SNPs in ADD3 were replicated as associated with BA (1.60E-04 ≤ P≤1.70E-04, 1.33 ≤ odds ratio (OR) ≤ 1.58 for rs17095355, 2.10E-04 ≤ P≤5.30E-04, 1.26 ≤ OR ≤ 1.57 for rs2501577). Though we failed to replicate the individual association of rs10509906 to disease, the intragenic epistatic effect between rs10509906 and rs2501577 was suggested as exhibiting susceptibility to BA, further cross-validated by multifactor dimensionality reduction (MDR) (P=0.068, OR = 1.37), which may explain extra hidden heritability of ADD3 to BA. Furthermore, through subclinical stratification, we also observed the association of risk to disease mainly came from the female patients.

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Hirschsprung’s disease (HSCR) is a neurodevelopmental disorder characterized by the absence of nerves in intestine with strong genetic components. SLC6A20 was found to be associated with HSCR in Korean population waiting for replication in an independent cohort. In the present study, ten single nucleotide polymorphisms (SNPs) in the SLC6A20 were selected from Southern Chinese with 1470 HSCR cases and 1473 ethnically matched healthy controls. Our results indicated that SNP rs7640009 was associated with HSCR and SLC6A20 has a gene–dose effect in the extent of the aganglionic segment during enteric nervous system (ENS) development. It is the first time to reveal the relationship between SNP rs2191026 and HSCR-associated enterocolitis (HAEC) susceptibility.

Biliary atresia (BA) is a genetic and severe fibro-inflammatory obliterative cholangiopathy of neonates. Platelet-derived growth factor subunit A (PDGFA), as one of participants in liver fibrosis, the overexpression of PDGFA through DNA hypomethylation may lead to the development of BA, but the pathogenesis is still unclear. We conducted a large case-control cohort to investigate the association of genetic variants in PDGFA with BA susceptibility in the Southern Chinese population (506 cases and 1473 controls). We observed that the G allele of rs9690350(G>C) in PDGFA was significantly associated with an increased risk of BA (OR=1.24, 95% CI=1.04-1.49, P=0.02). Additionally, the rs9690350 G allele increased the risk of non-cystic biliary atresia (OR=1.26, 95% CI=1.04-1.52, P=0.02) and was a genetic biomarker of severe manifestations after surgery. These findings indicate that the rs9690350 G allele is a PDGFA polymorphism associated with the risk of BA that may confer increased disease susceptibility.

Biliary atresia (BA) is the most common cause of endstage liver disease in infants with poor prognosis and high mortality. The etiology of BA is still unknown, but the genetic factors have been considered as an important player in BA. We investigated the association of two cis-regulated variants in CD14 (rs2569190) and NOTCH2 (rs835576) with BA susceptibility, using the largest case-control cohort, totaling 506 BA patients and 1,473 healthy controls in a Southern Chinese population. Significant epistatic interaction between the two variants in our samples was observed (p = 8.1E−03; OR = 2.78; 95% CI: 1.32–5.88). The expression of CD14 and NOTCH2 in the BA group was consistently lower than that in the control (CC) group (0.31 ± 0.02 versus 1.00 ± 0.14; p < 0.001), which might be related to the genetic susceptibility of the genes awaiting further validation.