Association of NRG1 and AUTS2 genetic polymorphisms with Hirschsprung disease in a South Chinese population

Abstract

Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of enteric ganglia. There are more than 15 genes identified as contributed to HSCR by family‐based or population‐based approaches. However, these findings were not fulfilled to explain the heritability of most sporadic cases. In this study, using 1470 HSCR and 1473 control subjects in South Chinese population, we replicated two variants in NRG1 (rs16879552, P = 1.05E‐04 and rs7835688, P = 1.19E‐07), and further clarified the two replicated SNPs were more essential for patients with short‐segment aganglionosis (SHSCR) (P = 2.37E‐05). We also tried to replicate the most prominent signal (rs7785360) in AUTS2, which was a potential susceptibility gene with HSCR. In our results, in terms of individual association, marginal effect was observed to affect the HSCR patients following recessive model (P = 0.089). Noteworthy, significant intergenic synergistic effect between rs16879552 (NRG1) and rs7785360 (AUTS2) was identified through cross‐validation by logistic regression (P = 2.45E‐03, OR = 1.53) and multifactor dimensionality reduction (MDR, P < 0.0001, OR = 1.77). Significant correlation was observed between expression of these two genes in the normal segments of the colons (P = 0.018), together with differential expression of these genes between aganglionic colonic segments and normal colonic segments of the HSCR patients (P value for AUTS2 <0.0001, P value for NRG1 = 0.0243). Although functional evaluation is required, we supply new evidence for the NRG1 to HSCR and raised up a new susceptibility gene AUTS2 to a specific symptom for the disease.

Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma

“…By contrast, most research to date reports an impact of common variants on only one or two of the subtypes. This inconsistency may be attributable to environmental and genetic diversity among different ethnicities [4,5,28].…”

“…Remarkably, this study is the first to propose a significant link between PHOX2B rs28647582 and the risk of all HSCR subtypes. Relationships between HSCR subtypes and PHOX2B have not been reported previously, though several common genetic variants in RET , EDNRB , and SOX10 reportedly associate with one or two of the subtypes [4,5,28]. The different HSCR subtypes reflect the severity of the intestinal neuronal precursor cell migration defect during embryonal development [35].…”

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.…”

Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease

“…Previous study have identified some susceptibility genes implicated in HSCR, such as RET , which is the major gene in HSCR with mutations found in most of the cases and was identified to be crucial for the development of neural crest cells thus involved in the pathogenesis of HSCR (Heanue et al, 2016; Porokuokka et al, 2018). In recent years, new susceptibility genes such as GLI , RELN, GAL , and AUTS2 have been found via gene screening (Liu et al, 2015; Wang et al, 2016, 2018; Zhang et al, 2018). This suggests that, genetic variations of HSCR are well-known and have been indentified in < 30% of HSCR cases, indicating the need to identify other variations involving in it (Bahrami et al, 2018).…”