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

Date Published: April 25, 2018

Publisher: Impact Journals

Author(s): Jinglu Zhao, Xiaoli Xie, Yuxiao Yao, Qiuming He, Ruizhong Zhang, Huimin Xia, Yan Zhang.


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.

Partial Text

Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction [1], defined by the partial or complete absence of the neural crest cells in the intestinal tract [2]. The overall prevalence of HSCR among the Asian population is estimated at 2.8/10,000 live births and displayed a significant racial variation [3].HSCR can be classified into three types based on the length of the aganglionic tract, including short-segment HSCR (S-HSCR), long-segment HSCR (L-HSCR) and total colonic aganglionosis (TCA) with the percentages around 80%, 15% and 5% respectively [4,5]. HSCR is a complex multifactorial disease, which is mainly determined by individual genetic factors [6,7]. The recurrence risk in siblings varied from 1% to 33% depending on the length of the aganglionic segments and gender of the probands. More than ten genes were identified as contributed to the pathogenesis of HSCR including RET, GDNF, EDNRB, EDN3 and so on [8]. However, mutations in these genes account for only ∼50% of the known cases of HSCR [9].

HSCR is a complex clinical syndrome. Increasing studies focused on case-control and trio based study designs. It the largest population-based study to the correlation of VAMP5 and MCC genetic polymorphisms with HSCR risk in our study that 1473 cases and 1470 unrelated controls were enrolled in. We have replicated two SNPs rs10206961 and rs14242 in VAMP5 that were associated with HSCR (Tables 1, 2). In further subclinical manifestation analysis, we further clarified SNPs rs10206961 and rs1254900 in VAMP5 and found they were essential for patients with LHSCR (Tables 3, 5). Interestingly, SNP interaction confirmed through logistic regression and multifactorial dimensionality reduction analysis revealed that the genotypes of the polymorphisms of VAMP5 rs1254900 and MCC rs11241200 were interacting significantly, thereby contributing to the risk of SHSCR (Table 4).




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