Sage Journals: Discover world-class research

Abstract

Objective

Hirschsprung disease (HSCR) originates from disruption of normal neural crest cell migration, differentiation, and proliferation during the fifth to eighth weeks of gestation. This results in the absence of intestinal ganglion cells in the distal intestinal tract. However, genetic variations affecting embryonic development of intestinal ganglion cells are unclear. Therefore, this study aimed to investigated the potential value of miR-492 rs2289030 G>C as a marker of susceptibility to HSCR

Methods

In this case–control study in southern Chinese children, we collected samples from 1473 controls and 1470 patients with HSCR. TaqMan genotyping of miR-492 rs2289030 G>C was performed by real-time fluorescent quantitative polymerase chain reaction.

Results

Multivariate logistic regression analysis showed that there was no significant association between the presence of the miR-492 rs2289030 G>C polymorphism and susceptibility to HSCR by evaluating the values of pooled odds ratios and 95% confidence intervals. Similarly, among different HSCR subtypes, rs2289030 G>C was also not associated with HSCR in hierarchical analysis.

Conclusions

Our results suggest that the miR-492 rs2289030 G>C polymorphism is not associated with susceptibility to HSCR in southern Chinese children. These results need to be further confirmed by investigating a more diverse ethnic population of patients with HSCR.

Keywords

rs2289030 polymorphism Hirschsprung disease susceptibility intestinal ganglion cells

Introduction

Hirschsprung disease (HSCR) is a common congenital gastrointestinal disease that is affected by genetics. The absence of intestinal ganglion cells in the distal intestinal tract is a major risk factor and a pivotal pathological feature of HSCR. Gastrointestinal motor function is mainly regulated by the enteric nervous system (ENS), and the absence or abnormal function of the ENS can lead to gastrointestinal dysfunction. Because of congenital loss of ganglion cells in the intestine of the distal colon, anal canal, or rectum, this intestinal segment cannot produce normal intestinal peristalsis.^1–4 The clinical symptoms of these patients mainly include delayed meconium discharge, abdominal distension, bloody stool, fever, and biliary vomiting. At present, the main treatment for HSCR is to remove the intestinal tract or ostomy.⁵,⁶ However, impaired bowel function with poor prognosis has a negative effect on patients’ quality of life. For these reasons, identification of the main molecules involved in HSCR is urgent for improving the clinical outcome. A growing number of genes and genetic pathways that play a critical functional role in neural crest cell development have been confirmed to be related to the pathogenesis of HSCR.²,^7–9. However, mutations in genes account for only approximately half of the known mutations found in patients with HSCR.¹⁰,¹¹

Methylation and histone modification have critical roles in embryonic development and neurogenesis.²,⁹ Particularly, DNA methyltransferase 3B and methyl CpG-binding protein 2 expression are downregulated in neural stem cells obtained from patients with HSCR, which results in lower global DNA methylation.¹²,¹³ Moreover, the protein complex homeobox B5 can regulate RET by changing chromatin conformation.¹⁴ Additionally, GDNF family receptor alpha-4 has been widely proposed as an HSCR susceptibility gene.¹⁵ Although the interaction between genetic modification factors, including methylation and histone modification, may reflect the pathogenesis of HSCR, the role of epitranscriptomics in this pathogenesis remains to be further explored.

Epitranscriptomics refers to RNA modifications/functional alterations in the transcriptome that do not change the ribonucleotide sequence.⁸,¹⁶ MicroRNAs (miRNAs) are a class of single-stranded, small molecule RNAs that are derived from noncoding regions of chromosomes. These miRNAs can act as either an oncogene or a tumor suppressor to regulate a variety of biological processes, such as development, inflammation, and tumorigenesis.¹⁷,¹⁸ The miRNA miR-492 is involved in regulating progression of hepatic cancer by targeting phosphatase and tensin homolog.¹⁹ Furthermore, miR-492 may be regulated by the hepatoblastoma marker gene keratin 19 and play an important role in progression of malignant embryonic liver tumors.²⁰ Wu et al.²¹ reported that miR-492 was involved in regulating psoriasis by suppressing the basigin protein. Genetic variations of miRNA genes or polymorphisms have important significance and potential value for identifying high-risk individuals, diagnosing patients early, and using interventions in development and susceptibility of disease.^22–24 However, the polymorphisms of miR-492 have not been investigated in case–control studies related to HSCR. A polymorphism of miR-492 may affect migration of embryonic intestinal neural crest cells. Therefore, we aimed to investigate the association of the miR-492 rs2289030 G>C single nucleotide polymorphism (SNP) and the risk of HSCR in southern Chinese children in a case–control study.

Materials and methods

Patients

Our study was prospectively conducted and planned as a case–control study. We included southern Chinese children with HSCR and controls who were recruited from the Guangzhou Women and Children’s Medical Center from February 2010 to November 2015.^25–27 The controls were children who were matched geographically and ethnically with children with HSCR and had no history of HSCR or neurological disorders. According to the relevant regulations, this study was approved by the institutional review board of Guangzhou Women and Children’s Medical Center (Ethical approval No. 201943800). All patients were diagnosed with HSCR via a histopathological examination and clinical imaging diagnosis. Clinical information was collected through medical records, and all subjects or their guardians signed informed consent forms.

Genotyping of the miR-492 rs2289030 G>C SNP

On the basis of our previous criteria,²⁸,²⁹ in the present case-control study, we selected the potential rs2289030 G>C polymorphic locus of miR-492. Using a TIANamp Blood DNA Kit (DP348; TianGen Biotech Co., Ltd., Beijing, China) and TIANquick FFPE DNA Kit (DP330; TianGen Biotech Co., Ltd.), DNA was extracted from peripheral blood leukocytes of all participants and paraffin-embedded samples of the patients’ intestines. DNA samples were diluted to 5 ng/mL in 96-well plates and stored at −20°C for later use. DNA samples were then added to TaqMan Genotyping PCR PreMix (probe) (FP211; TianGen Biotech Co., Ltd.) in 384-well plates. Real-time fluorescent quantitative polymerase chain reaction was used to detect genotyping of the miR-492 rs2289030 G>C SNP.^30–32 At least 10% of samples were randomly selected for repeated genotyping and the same genotypic results were obtained.

Statistical analysis

Differences in demographic characteristics and distribution of genotype frequency between patients with HSCR and controls were assessed using the bilateral χ² test. The Hardy–Weinberg equilibrium was used to assess the genotype frequencies of the goodness-of-fit χ² test in the controls. Measurement data are presented as the mean ± standard deviation. Multivariate logistic regression was used to adjust for the effects of age and sex. The association between the miR-492 SNP and susceptibility of HSCR was estimated by multivariate logistic regression analysis using odds ratios (ORs) and 95% confidence intervals (CIs). Furthermore, stratified analyses were performed to calculate different subtypes of HSCR on the basis of the length of the aganglionic tract. All statistical analyses and tests were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA). Statistical significance was set at P < 0.05.

Results

Baseline demographics

We studied 1470 southern Chinese children with HSCR (mean age: 8.37 ± 20.50 months; 83.67% boys) and 1473 controls (mean age: 18.61 ± 19.75 months; 34.35% girls).

Association of the miR-492 SNP with susceptibility of HSCR

Using real-time fluorescent quantitative polymerase chain reaction, we successfully genotyped the miR-492 rs2289030 G>C SNP in 1428 patients and 1463 controls. The distribution of genotype frequency of miR-492 rs2289030 G>C was consistent with the Hardy–Weinberg equilibrium (rs2289030 G>C, P=0.059) in the controls. We found that the genotype results in patients with HSCR were not significantly different compared with those of the controls. Therefore, none of the rs2289030 genotypes were associated with susceptibility to HSCR ( Table 1 ).

Table 1.

Association between the miR-492 rs2289030 G>C polymorphism and susceptibility of Hirschsprung disease.

Genotype	Patients(n = 1428)	Controls (n = 1463)	P ^a	Crude OR(95% CI)	P	Adjusted OR(95% CI)^b	P ^b
rs2289030 G>C (HWE = 0.059)
GG	784 (54.90)	828 (56.60)		1.00		1.00
GC	545 (38.17)	527 (36.02)		1.09 (0.94–1.28)	0.263	1.09 (0.93–1.28)	0.286
GG	99 (6.93)	108 (7.38)		0.97 (0.73–1.29)	0.827	0.94 (0.70–1.28)	0.707
Additive			0.594	1.03 (0.92–1.16)	0.594	1.03 (0.91–1.16)	0.691
Dominant	644 (45.10)	635 (43.40)	0.359	1.07 (0.93–1.24)	0.359	1.07 (0.92–1.24)	0.411
Recessive	1329 (93.07)	1355 (92.62)	0.639	0.94 (0.70–1.24)	0.640	0.91 (0.68–1.22)	0.537

OR, odds ratio; CI, confidence interval; HWE, Hardy–Weinberg equilibrium.

^aχ² test for the distribution of genotype between patients with Hirschsprung disease and controls.

^bAdjusted for age and sex.

Stratification analysis of the risk between miR-492 rs2289030 G>C and different HSCR subtypes

Anatomically, HSCR was divided into three categories of short-segment HSCR, long-segment HSCR, and total colonic aganglionosis on the basis of differences in distal intestinal vascular malformations.⁴,⁵,³³ After adjusting for age and sex, we found that there were no significant associations between miR-492 rs2289030 G>C and the three HSCR subtypes (Table 2). This finding suggests that the miR-492 rs2289030 G>C SNP is not associated with susceptibility to HSCR.

Table 2.

Stratification analysis of the association between miR-492 rs2289030 G>C and susceptibility of Hirschsprung disease by subtype.

Variable	rs2289030 (patients/controls)		Crude OR	P	Adjusted OR^a	P ^a
	GG	GC/CC	(95% CI)		(95% CI)
SHCSR	554/828	453/635	1.07 (0.91–1.25)	0.436	1.07 (0.91–1.27)	0.427
LHCSR	157/828	127/635	1.06 (0.82–1.36)	0.683	1.03 (0.79–1.35)	0.813
TCA	45/828	33/635	0.96 (0.60–1.52)	0.849	0.94 (0.58–1.51)	0.790

OR, odds ratio; CI, confidence interval; SHCSR, short-segment Hirschsprung disease; LHCSR, long-segment Hirschsprung disease; TCA, total colonic aganglionosis.

^aAdjusted for age and sex by omitting the corresponding stratification factor.

Discussion

The complex subclinical manifestations of HSCR and the unclear pathogenesis of this disease limit the development of personalized diagnosis and treatment.⁴,⁸ In our case–control study of southern Chinese children, we investigated the association between an miR-492 SNP and susceptibility to HSCRs. To the best of our knowledge, rs2289030 G>C has not been examined in any previous studies on HSCR. Our study showed that miR-492 rs2289030 G>C was not significantly associated with a risk of HSCR in southern Chinese children.

With advancement in research and technology, an increasing number of scholars believe that genetic factors play an important role in the development of HSCR. The genetic susceptibility of different individuals greatly varies. The major gene for HSCR encodes the receptor tyrosine kinase RET. The T variant of RET (RET rs2435357 C>T) can increase penetrance in patients with HSCR and RET coding mutations.³⁴ RET mutations affect the binding of RET to its ligands GDNF, neurturin, artemin, and persephin, leading to migration and differentiation disorders of neural crest stem cells.¹⁰,³⁵ Many studies have investigated the potential functional genetic variation sites and their genetic susceptibilities to HSCR.¹,⁴,⁵,⁸,³⁶,³⁷ Passarge and Lyonnet et al. suggested that a dominant gene for HSCR maps to 10q11.2, which encodes the RET receptor.^38–40 Additionally, semaphorin 3 and neuregulin 1 (NRG1) were also discovered in Europeans and Asians by genome-wide association study analysis.⁴¹,⁴² These genes can affect migration, differentiation and viability of neuronal cells by binding to specific receptors. Subsequently, other researchers reported the existence of a cumulative genetic risk for HSCR susceptibility from RET (rs2506030 or rs2435357) and NRG1 (rs2439302) polymorphisms in the Chinese population.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. Discovering SNPs and genetic mutations and determining their biological functions will help to understand the etiology of this disease.

A growing amount of research has shown that noncoding RNAs are potential markers of disease risk and prognosis in various diseases.²,⁸,³⁶,³⁷,^45–47 A decrease in miR-141 can target downstream genes, increasing the expression of integrin-associated protein and cullin 3, which play important roles in inhibiting cell migration and proliferation during the pathogenesis of HSCR.⁴⁸ The miRNA miRNA-206 has also been shown to be downregulated and targets fibronectin 1 (FN1), serum deprivation response, and paired box 3 in Chinese patients with HSCR.⁴⁹ In contrast, Gunadi et al.⁵⁰ reported an increase in miRNA-206 levels in Indonesian patients with HSCR. These authors showed that fibronectin 1 gene expression was significantly increased in Indonesian HSCR. Moreover, paired box 3 gene expression was not different between Indonesian patients with HSCR and the control group. Thus, the conflicting miRNA-206 expression pattern in patients with HSCR and controls is mainly attributed to different detection levels and selection bias, with a genetically distinct group within Asia.

Nonetheless, whether miR-492 is involved in the pathogenesis of HSCR has yet to be determined. miR-492 affects proliferation, migration and invasion of hepatoblastoma by regulating cluster of differentiation 44 (CD44).⁵¹ Furthermore, miR-492 plays a role in promoting tumor cell growth by regulating suppressor of cytokine signaling 2, SRY-related high mobility group-box transcription factor 7, CD147, and p21-activated kinase 7 (PAK7).^52–55 Intriguingly, PAK7, which belongs to the p21-activated kinase family, is a highly conserved family of serine/threonine protein kinases that are regulated by Ras-related small G-proteins, such as Cdc42 and Rac1.⁵⁶ Ding et al. observed that PAK activation inhibited expression of endogenous nischarin and promoted growth of rat cortical neurites.⁵⁷ Moreover, PAK7 regulates the differentiation of oligodendrocyte precursor cells, which are myelin-forming cells of the central nervous system.⁵⁸ Collectively, these reports raised the question of whether miR-492 can directly interact with phosphorylated PAK7 and regulate migration or differentiation of neural crest cells in the pathogenesis of HSCR.

Yu et al. reported⁵⁹ that patients carrying the miR-492 rs2289030 C>G genotype had a significantly reduced risk of hepatocellular carcinoma. The miRNAs are short (20–24 nt) noncoding RNAs that are involved in posttranscriptional regulation of gene expression in multicellular organisms by affecting the stability and translation of mRNA. Because of the location of rs2289030 G>C in the transcription factor binding sites of miR-492, its functional regulatory role might be important. To determine whether this marker is a putative genetic factor that also confers susceptibility to HSCR, we analyzed the relationship between miR-492 rs2289030 G>C and susceptibility of HSCR in southern Chinese children. However, we did not find an association between miR-492 rs2289030 G>C and susceptibility of HSCR. Nevertheless, we cannot exclude the implication of other polymorphisms within miR-492 in pathogenesis of HSCR. There is still a lack of research on miR-492 and susceptibility mechanisms of HSCR, which has potential implications for HSCR therapy. Additionally, there are some differences in the etiology of this disease and genetic susceptibility among different ethnicities. Because all of the recruited subjects in this study were Han Chinese living in southern China, some of our results are not completely consistent with previous studies in other ethnic populations, such as Caucasians or Koreans.^59–61 This inconsistency between studies may be attributed to genetic variations and living environments between different ethnic groups.⁶² Because of the possible differences in allele frequencies and SNP linkage imbalance patterns among different populations, only the rs2289030 C>G SNP from the miR-492 gene was selected for association analysis in the current study. More gene polymorphisms should be further investigated in the future. The incidence of neonatal HSCR is approximately 1/5000. In this study, we did not perform a sample size calculation, and the limited number of samples may have affected the significance of our results.

In summary, the miR-492 rs2289030 G>C SNP is not associated with the risk of HSCR in southern Chinese children. The role of other SNPs in the pathogenesis of HSCR needs to be further examined. Future research should target studying genetic variants identified in HSCR to identify penetrance and the clinical effect. This may ultimately lead to better screening programs and prevention of HSCR.

Footnotes

Authors' contributions

Wei Zhong conceived and designed the study. Yi Zheng, Mi Wang, Yanqing Liu, Qiuming He, Xiaoli Xie, Lifeng Lu, and Wei Zhong collected samples and data. Yanqing Liu and Mi Wang provided technical support. Yi Zheng, Mi Wang, and Lifeng Lu collected and processed the data, and conducted experiments. Yi Zheng and Xiaoli Xie analyzed the data. Xiaoli Xie prepared all of the tables. Yi Zheng, Yanqing Liu, Mi Wang, and Wei Zhong wrote the manuscript. All authors approved the final manuscript.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by grants from the Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center (No. 1600019), the Natural Science Foundation of Guangdong Province, China (No: 2019A1515010971), and Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease (No: 2019B030301004).

ORCID iD

Wei Zhong

References

Luzon-Toro

Villalba-Benito

Torroglosa

, et al. What is new about the genetic background of Hirschsprung disease? Clin Genet 2020; 97: 114–124. DOI: 10.1111/cge.13615.

Torroglosa

Villalba-Benito

Luzon-Toro

, et al. Epigenetic Mechanisms in Hirschsprung Disease. Int J Mol Sci 2019; 20: 3123. DOI: 10.3390/ijms20133123.

Lake

Heuckeroth

RO.

Enteric nervous system development: migration, differentiation, and disease.

Am J Physiol Gastrointest Liver Physiol 2013; 305: G1–24. DOI: 10.1152/ajpgi.00452.2012.

Fattahi

Steinbeck

Kriks

, et al. Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease. Nature 2016; 531: 105–109. DOI: 10.1038/nature16951.

Amiel

Sproat-Emison

Garcia-Barcelo

, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet 2008; 45: 1–14. DOI: 10.1136/jmg.2007.053959.

Heuckeroth

RO.

Hirschsprung disease – integrating basic science and clinical medicine to improve outcomes.

Nat Rev Gastroenterol Hepatol 2018; 15: 152–167. DOI: 10.1038/nrgastro.2017.149.

Workman

Mahe

Trisno

, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 2017; 23: 49–59. DOI: 10.1038/nm.4233.

Jaroy

Acosta-Jimenez

Hotta

, et al. “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease - a review. Clin Epigenetics 2019; 11: 135. DOI: 10.1186/s13148-019-0718-x.

Torroglosa

Alves

Fernandez

, et al. Epigenetics in ENS development and Hirschsprung disease. Dev Biol 2016; 417: 209–216. DOI: 10.1016/j.ydbio.2016.06.017.

10.

Parisi

Kapur

RP.

Genetics of Hirschsprung disease.

Curr Opin Pediatr 2000; 12: 610–617. DOI: 10.1097/00008480-200012000-00017.

11.

Butler Tjaden

Trainor

PA.

The developmental etiology and pathogenesis of Hirschsprung disease.

Transl Res 2013; 162: 1–15. DOI: 10.1016/j.trsl.2013.03.001.

12.

Berdasco

Esteller

DNA methylation in stem cell renewal and multipotency.

Stem Cell Res Ther 2011; 2: 42. DOI: 10.1186/scrt83.

13.

Villalba-Benito

Torroglosa

Fernandez

, et al. Overexpression of DNMT3b target genes during Enteric Nervous System development contribute to the onset of Hirschsprung disease. Sci Rep 2017; 7: 6221. DOI: 10.1038/s41598-017-06539-8.

14.

Zhu

Kam

Garcia-Barcelo

, et al. HOXB5 binds to multi-species conserved sequence (MCS + 9.7) of RET gene and regulates RET expression. Int J Biochem Cell Biol 2014; 51: 142–149. DOI: 10.1016/j.biocel.2014.04.013.

15.

Wang

Zhang

Wang

, et al. Demethylation of GFRA4 Promotes Cell Proliferation and Invasion in Hirschsprung Disease. DNA Cell Biol 2018; 37: 316–324. DOI: 10.1089/dna.2017.3928.

16.

Piletic

Kunej

MicroRNA epigenetic signatures in human disease.

Arch Toxicol 2016; 90: 2405–2419. DOI: 10.1007/s00204-016-1815-7.

17.

Bushati

Cohen

SM.

MicroRNA functions.

Annu Rev Cell Dev Biol 2007; 23: 175–205. DOI: 10.1146/annurev.cellbio.23.090506.123406.

18.

Mohr

Mott

JL.

Overview of microRNA biology.

Semin Liver Dis 2015; 35: 3–11. DOI: 10.1055/s-0034-1397344.

19.

Jiang

Zhang

, et al. MicroRNA-492 expression promotes the progression of hepatic cancer by targeting PTEN. Cancer Cell Int 2014; 14: 95. DOI: 10.1186/s12935-014-0095-7.

20.

von Frowein

Pagel

Kappler

, et al. MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma. Hepatology 2011; 53: 833–842. DOI: 10.1002/hep.24125.

21.

Sun

, et al. A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population. Hum Genet 2011; 130: 749–757. DOI: 10.1007/s00439-011-1026-5.

22.

Imanishi

Ikegami

Nishioka

, et al. [The effects of thromboxane A2 synthetase inhibitor on chronic rejection of kidney transplantation]. Nihon Hinyokika Gakkai Zasshi 1990; 81: 895–901. DOI: 10.5980/jpnjurol1989.81.895.

23.

Liang

Wang

, et al. Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Hum Mutat 2009; 30: 79–84. DOI: 10.1002/humu.20837.

24.

de Larrea

Navarro

Tejero

, et al. Impact of MiRSNPs on survival and progression in patients with multiple myeloma undergoing autologous stem cell transplantation. Clin Cancer Res 2012; 18: 3697–3704. DOI: 10.1158/1078-0432.CCR-12-0191.

25.

Zhang

, et al. Large-scale replication study identified multiple independent SNPs in RET synergistically associated with Hirschsprung disease in Southern Chinese population. Aging (Albany NY) 2017; 9: 1996–2009. DOI: 10.18632/aging.101294.

26.

Wang

Zhang

, et al. Association between DSCAM polymorphisms and non-syndromic Hirschsprung disease in Chinese population. BMC Med Genet 2018; 19: 116. DOI: 10.1186/s12881-018-0637-2.

27.

Zhao

Xie

Yao

, et al. Association of VAMP5 and MCC genetic polymorphisms with increased risk of Hirschsprung disease susceptibility in Southern Chinese children. Aging (Albany NY) 2018; 10: 689–700. DOI: 10.18632/aging.101423.

28.

Qiu

Wang

, et al. Polymorphisms in the XPG gene and risk of gastric cancer in Chinese populations. Hum Genet 2012; 131: 1235–1244. DOI: 10.1007/s00439-012-1152-8.

29.

Liu

Hua

, et al. MYC gene associated polymorphisms and Wilms tumor risk in Chinese children: a four-center case-control study. Ann Transl Med 2019; 7: 475. DOI: 10.21037/atm.2019.08.31.

30.

Wang

Zhu

, et al. Association of potentially functional variants in the XPG gene with neuroblastoma risk in a Chinese population. Journal of cellular and molecular medicine 2016; 20: 1481–1490. DOI: 10.1111/jcmm.12836.

31.

Yang

Zhang

, et al. Potentially functional polymorphisms in the LIN28B gene contribute to neuroblastoma susceptibility in Chinese children. Journal of cellular and molecular medicine 2016; 20: 1534–1541. DOI: 10.1111/jcmm.12846.

32.

Zhang

, et al. LMO1 super-enhancer polymorphism rs2168101 G>T correlates with decreased neuroblastoma risk in Chinese children. Journal of Cancer 2018; 9: 1592–1597. DOI: 10.7150/jca.24326.

33.

Das

Mohanty

Hirschsprung Disease – Current Diagnosis and Management.

Indian J Pediatr 2017; 84: 618–623. DOI: 10.1007/s12098-017-2371-8.

34.

Emison

Garcia-Barcelo

Grice

, et al. Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability. Am J Hum Genet 2010; 87: 60–74. DOI: 10.1016/j.ajhg.2010.06.007.

35.

Takahashi

The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 2001; 12: 361–373. DOI: 10.1016/s1359-6101(01)00012-0.

36.

Sergi

Caluseriu

McColl

, et al. Hirschsprung's disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives. Pediatr Res 2017; 81: 177–191. DOI: 10.1038/pr.2016.202.

37.

Rogers

JM.

Search for the missing lncs: gene regulatory networks in neural crest development and long non-coding RNA biomarkers of Hirschsprung's disease.

Neurogastroenterol Motil 2016; 28: 161–166. DOI: 10.1111/nmo.12776.

38.

Lyonnet

Bolino

Pelet

, et al. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nat Genet 1993; 4: 346–350. DOI: 10.1038/ng0893-346.

39.

Passarge

Wither polygenic inheritance: mapping Hirschsprung disease.

Nat Genet 1993; 4: 325–326. DOI: 10.1038/ng0893-325.

40.

Passarge

Dissecting Hirschsprung disease.

Nat Genet 2002; 31: 11–12. DOI: 10.1038/ng878.

41.

Garcia-Barcelo

Tang

Ngan

, et al. Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease. Proc Natl Acad Sci U S A 2009; 106: 2694–2699. DOI: 10.1073/pnas.0809630105.

42.

Jiang

Arnold

Heanue

, et al. Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability. Am J Hum Genet 2015; 96: 581–596. DOI: 10.1016/j.ajhg.2015.02.014.

43.

Yang

, et al. Effects of RET, NRG1 and NRG3 Polymorphisms in a Chinese Population with Hirschsprung Disease. Sci Rep 2017; 7: 43222. DOI: 10.1038/srep43222.

44.

Shin

Kim

Seo

, et al. Potential association of VAMP5 polymorphisms with total colonic aganglionosis in Hirschsprung disease. Neurogastroenterol Motil 2016; 28: 1055–1063. DOI: 10.1111/nmo.12807.

45.

Ding

Yuan

, et al. MiRNA Polymorphisms and Cancer Prognosis: A Systematic Review and Meta-Analysis. Front Oncol 2018; 8: 596. DOI: 10.3389/fonc.2018.00596.

46.

Alidoust

Hamzehzadeh

Rivandi

, et al. Polymorphisms in non-coding RNAs and risk of colorectal cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2018; 132: 100–110. DOI: 10.1016/j.critrevonc.2018.09.003.

47.

Wang

Guo

, et al. miRNA Profiling Reveals Dysregulation of RET and RET-Regulating Pathways in Hirschsprung's Disease. PLoS One 2016; 11: e0150222. DOI: 10.1371/journal.pone.0150222.

48.

Tang

Qin

Tang

, et al. Aberrant reduction of MiR-141 increased CD47/CUL3 in Hirschsprung's disease. Cell Physiol Biochem 2013; 32: 1655–1667. DOI: 10.1159/000356601.

49.

Sharan

Zhu

Xie

, et al. Down-regulation of miR-206 is associated with Hirschsprung disease and suppresses cell migration and proliferation in cell models. Sci Rep 2015; 5: 9302. DOI: 10.1038/srep09302.

50.

Gunadi, Budi

NYP

Kalim

, et al. Aberrant expressions of miRNA-206 target, FN1, in multifactorial Hirschsprung disease. Orphanet J Rare Dis 2019; 14: 5. DOI: 10.1186/s13023-018-0973-5.

51.

von Frowein

Hauck

Kappler

, et al. MiR-492 regulates metastatic properties of hepatoblastoma via CD44. Liver Int 2018; 38: 1280–1291. 2018/01/10. DOI: 10.1111/liv.13687.

52.

Peng

Zhu

Wang

, et al. MiR-492 is functionally involved in Oxaliplatin resistance in colon cancer cells LS174T via its regulating the expression of CD147. Mol Cell Biochem 2015; 405: 73–79. DOI: 10.1007/s11010-015-2397-z.

53.

Shen

Cai

Feng

, et al. MiR-492 contributes to cell proliferation and cell cycle of human breast cancer cells by suppressing SOX7 expression. Tumour Biol 2015; 36: 1913–1921. DOI: 10.1007/s13277-014-2794-z.

54.

Shi

Liang

, et al. MiR-492 exerts tumor-promoting function in prostate cancer through repressing SOCS2 expression. Eur Rev Med Pharmacol Sci 2019; 23: 992–1001. DOI: 10.26355/eurrev_201902_16986.]

55.

Song

Xie

Liu

, et al. MicroRNA-492 overexpression exerts suppressive effects on the progression of osteosarcoma by targeting PAK7. Int J Mol Med 2017; 40: 891–897. DOI: 10.3892/ijmm.2017.3046.

56.

Wang

Lei

, et al. The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration. Br J Pharmacol 2018; 175: 1362–1374. DOI: 10.1111/bph.13872.

57.

Ding

, et al. Inhibition of Nischarin Expression Promotes Neurite Outgrowth through Regulation of PAK Activity. PLoS One 2015; 10: e0144948. DOI: 10.1371/journal.pone.0144948.

58.

Maglorius Renkilaraj

MRL

Baudouin

Wells

, et al. The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation. Neurobiol Dis 2017; 98: 137–148. DOI: 10.1016/j.nbd.2016.12.004.

59.

Xiao

, et al. miR-492G>C polymorphism (rs2289030) is associated with overall survival of hepatocellular carcinoma patients. Tumour Biol 2016; 37: 8961–8972. DOI: 10.1007/s13277-015-4752-9.

60.

Lee

Kim

Chae

, et al. Prognostic impact of microRNA-related gene polymorphisms on survival of patients with colorectal cancer. J Cancer Res Clin Oncol 2010; 136: 1073–1078.

61.

Kupcinskas

Bruzaite

Juzenas

, et al. Lack of association between miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 gene polymorphisms and colorectal cancer. Sci Rep 2014; 4: 5993.

62.

Heuckeroth

Schafer

KH.

Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention.

Dev Biol 2016; 417: 188–197.

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

Abstract

Objective

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Patients

Genotyping of the miR-492 rs2289030 G>C SNP

Statistical analysis

Results

Baseline demographics

Association of the miR-492 SNP with susceptibility of HSCR

Stratification analysis of the risk between miR-492 rs2289030 G>C and different HSCR subtypes

Discussion

Footnotes

Authors' contributions

Declaration of conflicting interest

Funding

ORCID iD

References