Hedgehog gene polymorphisms are associated with the risk of Hirschsprung's disease and anorectal malformation in a Chinese population

Gao,Hong; Wang,Dajia; Bai,Yuzuo; Zhang,Juan; Wu,Mei; Mi,Jie; Jia,Huimin; Wang,Weilin

doi:10.3892/mmr.2016.5139

Hedgehog gene polymorphisms are associated with the risk of Hirschsprung's disease and anorectal malformation in a Chinese population

Authors:
- Hong Gao
- Dajia Wang
- Yuzuo Bai
- Juan Zhang
- Mei Wu
- Jie Mi
- Huimin Jia
- Weilin Wang
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Affiliations: Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of Pediatric Surgery, Jinzhou Women and Children's Hospital, Jinzhou, Liaoning 121000, P.R. China, Department of General Surgery, Children's Hospital of Hebei, Shijiazhuang, Hebei 050031, P.R. China
Published online on: April 15, 2016 https://doi.org/10.3892/mmr.2016.5139
Pages: 4759-4766

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Abstract

Hedgehog (HH) is one of the key morphogens expressed in the gut mesenchyme that control animal development and tissue homeostasis. The HH gene has been shown to be closely associated with Hirschsprung's disease (HSCR) and anorectal malformations (ARMs); thus, it was hypothesized that HH signaling pathway‑associated genes may be candidate genes for HSCR and ARMs. The present study aimed to evaluate whether polymorphisms in the HH gene were associated with HSCR and ARM in a Chinese population. HH gene variants (rs61730970, rs200798148 and rs146535482) were analyzed in whole blood samples from patients with HSCR and ARMs, as well as normal children (control group). The results suggested that, when the rs61730970, rs200798148 and rs146535482 alleles of the HH gene lacked particular single nucleotide polymorphisms (SNPs), the patients were associated with a greater risk of HSCR and/or ARM [HSCR: odds ratio (OR)=1.543, P=0.004; OR=1.494, P=0.007; rs146535482: OR=1.556, P=0.003, respectively. ARM: OR=1.528, P=0.045; OR=1.800, P=0.007; OR=1.743, P=0.009, respectively). Sequencing of rs61730970 and rs200798148 revealed a loss of heterozygosity and SNPs at these loci in patients with HSCR. Similarly, the sequencing of rs61730970 and rs146535482 revealed a loss of heterozygosity and SNPs at these loci in patients with ARM. Although preliminary, these results suggested that the HH gene may be involved in genetic interactions associated with the pathogenesis of HSCR and ARM.

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1	Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, et al: Hirschsprung disease, associated syndromes and genetics: A review. J Med Genet. 45:1–14. 2008. View Article : Google Scholar
2	Saeed A, Barreto L, Neogii SG, Loos A, McFarlane I and Aslam A: Identification of novel genes in Hirschsprung disease pathway using whole genome expression study. J Pediatr Surg. 47:303–307. 2012. View Article : Google Scholar : PubMed/NCBI
3	Passarge E and Bruder E: Genetic bases of Hirschsprung's disease. Pathologe. 28:113–118. 2007.In German. View Article : Google Scholar : PubMed/NCBI
4	El-Nachef W and Grikscheit T: Enteric nervous system cell replacement therapy for Hirschsprung disease: Beyond tissue-engineered intestine. Eur J Pediatr Surg. 24:214–218. 2014. View Article : Google Scholar : PubMed/NCBI
5	Rintala RJ: Congenital anorectal malformations: Anything new? J Pediatr Gastroenterol Nutr. 48(Suppl 2): S79–S82. 2009. View Article : Google Scholar : PubMed/NCBI
6	Bán G, Németh P and Túri S: Neurovesical dysfunction in children with anorectal malformations. Orv Hetil. 147:1645–1649. 2006.In Hungarian.
7	Sánchez-Mejías A, Fernández RM, López-Alonso M, Antiñolo G and Borrego S: New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet Med. 12:39–43. 2010. View Article : Google Scholar
8	Pan ZW, Lou J, Luo C, Yu L and Li JC: Association analysis of the SOX10 polymorphism with Hirschsprung disease in the Han Chinese population. J Pediatr Surg. 46:1930–1934. 2011. View Article : Google Scholar : PubMed/NCBI
9	Fernandez RM, Ruiz-Ferrer M, Lopez-Alonso M, Antiñolo G and Borrego S: Polymorphisms in the genes encoding the 4 RET ligands, GDNF, NTN, ARTN, PSPN, and susceptibility to Hirschsprung disease. J Pediatr Surg. 43:2042–2047. 2008. View Article : Google Scholar : PubMed/NCBI
10	Kwon MJ, Lee GH, Lee MK, Kim JY, Yoo HS, Ki CS, Chang YS, Kim JW and Park WS: PHOX2B mutations in patients with Ondine-Hirschsprung disease and a review of the literature. Eur J Pediatr. 170:1267–1271. 2011. View Article : Google Scholar : PubMed/NCBI
11	Gregory-Evans CY, Vieira H, Dalton R, Adams GG, Salt A and Gregory-Evans K: Ocular coloboma and high myopia with Hirschsprung disease associated with a novel ZFHX1B missense mutation and trisomy 21. Am J Med Genet A. 131:86–90. 2004. View Article : Google Scholar : PubMed/NCBI
12	Seifert AW, Harfe BD and Cohn MJ: Cell lineage analysis demonstrates an endodermal origin of the distal urethra and perineum. Dev Biol. 318:143–152. 2008. View Article : Google Scholar : PubMed/NCBI
13	van den Brink GR: Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol Rev. 87:1343–1375. 2007. View Article : Google Scholar : PubMed/NCBI
14	Torihashi S, Hattori T, Hasegawa H, Kurahashi M, Ogaeri T and Fujimoto T: The expression and crucial roles of BMP signaling in development of smooth muscle progenitor cells in the mouse embryonic gut. Differentiation. 77:277–289. 2009. View Article : Google Scholar : PubMed/NCBI
15	Zacchetti G, Duboule D and Zakany J: Hox gene function in vertebrate gut morphogenesis: The case of the cecum. Development. 134:3967–3973. 2007. View Article : Google Scholar : PubMed/NCBI
16	Fairbanks TJ, De Langhe S, Sala FG, Warburton D, Anderson KD, Bellusci S and Burns RC: Fibroblast growth factor 10 (Fgf10) invalidation results in anorectal malformation in mice. J Pediatr Surg. 39:360–365; discussion 360–365. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tai CC, Sala FG, Ford HR, Wang KS, Li C, Minoo P, Grikscheit TC and Bellusci S: Wnt5a knock-out mouse as a new model of anorectal malformation. J Surg Res. 156:278–282. 2009. View Article : Google Scholar : PubMed/NCBI
18	Ngan ES, Garcia-Barceló MM, Yip BH, Poon HC, Lau ST, Kwok CK, Sat E, Sham MH, Wong KK, Wainwright BJ, et al: Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans. J Clin Invest. 121:3467–3478. 2011. View Article : Google Scholar : PubMed/NCBI
19	Lees C, Howie S, Sartor RB and Satsangi J: The hedgehog signalling pathway in the gastrointestinal tract: Implications for development, homeostasis, and disease. Gastroenterology. 129:1696–1710. 2005. View Article : Google Scholar : PubMed/NCBI
20	Odent S, Atti-Bitach T, Blayau M, Mathieu M, Aug J, Delezo de AL, Gall JY, Le Marec B, Munnich A, David V and Vekemans M: Expression of the Sonic hedgehog (SHH) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum Mol Genet. 8:1683–1689. 1999. View Article : Google Scholar : PubMed/NCBI
21	Chan LH, Wang W, Yeung W, Deng Y, Yuan P and Mak KK: Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression. Oncogene. 33:4857–4866. 2014. View Article : Google Scholar
22	Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, et al: A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet. 131:565–579. 2012. View Article : Google Scholar :
23	Lu J, Yang L, Zhao H, Liu B, Li Y, Wu H, Li Q, Zeng B, Wang Y, Ji W and Zhou Y: The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in Southern and Eastern Chinese populations. Hum Mutat. 32:1299–1308. 2011. View Article : Google Scholar : PubMed/NCBI
24	Yang L, Li Y, Cheng M, Huang D, Zheng J, Liu B, Ling X, Li Q, Zhang X, Ji W, et al: A functional polymorphismatmi- croRNA-629-binding site in the 3′-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population. Carcinogenesis. 33:338–347. 2012. View Article : Google Scholar
25	Moore SW: Associations of anorectal malformations and related syndromes. Pediatr Surg Int. 29:665–676. 2013. View Article : Google Scholar : PubMed/NCBI
26	Ingham PW, Nakano Y and Seger C: Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet. 12:393–406. 2011. View Article : Google Scholar : PubMed/NCBI
27	McMahon AP, Ingham PW and Tabin CJ: Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 53:1–114. 2003. View Article : Google Scholar : PubMed/NCBI
28	Porter JA, Ekker SC, Park WJ, von Kessler DP, Young KE, Chen CH, Ma Y, Woods AS, Cotter RJ, Koonin EV and Beachy PA: Hedgehog patterning activity: Role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell. 86:21–34. 1996. View Article : Google Scholar : PubMed/NCBI
29	Porter JA, Young KE and Beachy PA: Cholesterol modification of hedgehog signaling proteins in animal development. Science. 274:255–259. 1996. View Article : Google Scholar : PubMed/NCBI
30	Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K, et al: Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem. 273:14037–14045. 1998. View Article : Google Scholar : PubMed/NCBI
31	Mann RK and Beachy PA: Novel lipid modifications of secreted protein signals. Annu Rev Biochem. 73:891–923. 2004. View Article : Google Scholar : PubMed/NCBI
32	Pettigrew CA, Asp E and Emerson CP Jr: A new role for Hedgehogs in juxtacrine signaling. Mech Dev. 131:137–149. 2014. View Article : Google Scholar :
33	Jiang SQ and Paulus H: A high-throughput, homogeneous, fluorescence polarization assay for inhibitors of hedgehog protein autoprocessing. J Biomol Screen. 15:1082–1087. 2010. View Article : Google Scholar : PubMed/NCBI
34	Tokhunts R, Singh S, Chu T, D'Angelo G, Baubet V, Goetz JA, Huang Z, Yuan Z, Ascano M, Zavros Y, et al: The full-length unprocessed hedgehog protein is an active signaling molecule. J Biol Chem. 285:2562–2568. 2010. View Article : Google Scholar :
35	Palm W, Swierczynska MM, Kumari V, Ehrhart-Bornstein M, Bornstein SR and Eaton S: Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals. PLoS Biol. 11:e10015052013. View Article : Google Scholar : PubMed/NCBI
36	Lee JD, Kraus P, Gaiano N, Nery S, Kohtz J, Fishell G, Loomis CA and Treisman JE: An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. Dev Biol. 233:122–136. 2001. View Article : Google Scholar : PubMed/NCBI