Association of VAMP5 and MCC genetic polymorphisms with increased risk of Hirschsprung disease susceptibility in Southern Chinese children

Abstract

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.

Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma

“…Hirschsprung’s disease (HSCR) is a congenital disorder characterized by a partial or complete absence of ganglion cells in the nerve plexuses of the lower digestive tract. The incidence is about 1/5,000 live births in Caucasians and about 1.4/5,000 of live births in Asians, and males are 3.5-4.0 times more likely to be affected than females [1]. HSCR is divided into three subtypes – short-segment HSCR (S-HSCR), long-segment HSCR (L-HSCR) and total colonic aganglionosis (TCA) – based on the length of the intestinal segment lacking nerve cells [2,3].…”

Association between miR-492 rs2289030 G>C and susceptibility to Hirschsprung disease in southern Chinese children

“…25,34,43 Furthermore, vesicle-associated membrane protein 5 rs1254900 and mutated in colorectal cancer rs11241200 contributed to the risk of HSCR by logistic regression and multifactor dimensionality reduction analyses in southern Chinese children and the Korean population. 27,44 These studies mentioned above indicate that SNPs may affect expression and function of target genes and may contribute to susceptibility of HSCR. Nonetheless, additional studies are required to improve the knowledge about the role of epigenetics in the pathogenesis of HSCR.…”

What is new about the genetic background of Hirschsprung disease?

“…Specifically, one SNP (c.73+9277C>T, rs2435357) within highly conserved enhancer like sequence intron 1 (MCS + 9.7) is most likely a low‐penetrant disease‐causing variant implicated in HSCR development . Recent studies described genetic interactions of associated variants between two genes and increased risk of HSCR …”

“…14,[57][58][59]62,63 Recent studies described genetic interactions of associated variants between two genes and increased risk of HSCR. 64,65 Several genetic variants within those genes that encode for GDNFfamily ligands and co-receptors have been associated with HSCR. A deletion with incomplete penetrance within GFRA1 was identified in two non-related families.…”