Research Article: Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma

Date Published: February 28, 2019

Publisher: Impact Journals

Author(s): Jinglu Zhao, Yun Zhu, Xiaoli Xie, Yuxiao Yao, Jiao Zhang, Ruizhong Zhang, Lihua Huang, Jiwen Cheng, Huimin Xia, Jing He, Yan Zhang.


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.

Partial Text

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]. As a result of extensive mutation screening in familial and sporadic patients, several genes are now known to be associated with HSCR, including RET, EDNRB, SOX10 and PHOX2B, among others [4,5]. Most of those genes have been implicated in the migration, differentiation, and maturation of enteric neural crest cells, and HSCR reflects the failure of enteric neural crest-derived cells to complete their anteroposterior migration to the end of the bowel [6].

HSCR and NB are neurocristopathies of the sympathetic and enteric nervous systems. HSCR is an aganglionosis with a strong genetic component affecting intestinal segments of various length. A number of genes are associated with HSCR, including PHOX2B, haploinsufficiency of which predisposes people to defects in intestinal development and function [19,29]. Since PHOX2B was first found to be associated with HSCR in 2003, eight PHOX2B SNPs have been reported [24,30,31]. However, not all patient populations exhibited a significant association between PHOX2B and HSCR [23–26]. In the present study, we confirmed the significant association between PHOX2B rs28647582 and HSCR in a Southern Chinese population of 1470 cases, which is a much larger sample than in earlier studies. Moreover, our findings predict an increased risk for every subtype of HSCR.




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