Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma

Abstract

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.

What is new about the genetic background of Hirschsprung disease?

“…The protein is involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype . It plays a major role on the Congenital Central Hypoventilation Syndrome (CCHS or Ondine's curse), that is frequently linked to HSCR, as well as on the onset of tumors with neural crest origin because of it is implication on the development of neural crest‐derived structures . This is in concordance with the concept that PHOX2B haploinsufficiency predisposes to HSCR.…”

<p>Negative Association Between lncRNA <em>HOTTIP</em> rs3807598 C>G and Hirschsprung Disease</p>

“…Relevant subjects' descriptions with details could be found in the previously published studies. 30,31 This study was conducted in accordance with the Declaration of Helsinki.…”

miR-618 rs2682818 C&gt;A polymorphism decreases Hirschsprung disease risk in Chinese children

“…HSCR is characterized by siblings whose risk of recurrence is 3-17%, with different incidence rates being significantly associated with gender, ganglion segment length and familial [10,11]. In recent years, more than a dozen genes related to the pathogenesis of HSCR were confirmed, including RET [12], EDNRB [13], SOX10 [14], GDNF [15], EDN3 [16], PHOX2B [17,18], etc. However, these gene mutations associated with the onset of HSCR are only half of current HSCR cases [6].…”