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Mol Biol Rep. 2017 Jul;44(3):307-313. doi: 10.1007/s11033-017-4111-6. Epub 2017 Jun 29.

Potential association between ITPKC genetic variations and Hirschsprung disease.

Author information

1
Research Institute for Basic Science, Sogang University, Seoul, 04107, Republic of Korea.
2
Department of Surgery, Konkuk University Medical Center, Seoul, 05030, Republic of Korea.
3
Department of Life Science, Sogang University, Seoul, 04107, Republic of Korea.
4
Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, 04107, Republic of Korea.
5
Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea.
6
Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
7
Department of Pediatric Surgery, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
8
Department of Pediatric Surgery, Seoul National University Children's Hospital, Seoul, 03080, Republic of Korea.
9
Department of Surgery, Jeju National University Hospital, Jeju, 63241, Republic of Korea.
10
Research Institute for Basic Science, Sogang University, Seoul, 04107, Republic of Korea. hdshin@sogang.ac.kr.
11
Department of Life Science, Sogang University, Seoul, 04107, Republic of Korea. hdshin@sogang.ac.kr.

Abstract

Hirschsprung disease (HSCR) is a congenital and complex disorder characterized by intestinal obstruction due to the absence of enteric neurons along variable lengths of the hindgut. Our recent genome-wide association study (GWAS) has revealed regional associations with HSCR at several loci of inositol-trisphosphate 3-kinase C (ITPKC). For fine mapping, we additionally selected and genotyped a total of 12 single nucleotide polymorphisms (SNPs) of ITPKC in 187 HSCR patients and 283 unaffected controls, and performed a further combined imputation analysis based on genotype data from this second stage of fine mapping and our previous GWAS stage, totaling 902 subjects (187 HSCR cases and 715 controls). As a result, several SNPs (minimum Pā€‰=ā€‰0.004) and a haplotype (Pā€‰=ā€‰0.02) were found to be significantly associated with HSCR. In further in silico analyses to ascertain the potential functions of the significant variants, the change from the common allele to the rare allele of the highly conserved nonsynonymous rs76785336 showed a difference in mRNA folding structure. In the case of intronic SNPs, rs2607420 with a high consensus value was predicted to be a new splice site. Although this study has limitations (such as lack of functional evaluations, small number of cases, and further need of replication in other cohorts), our findings suggest that genetic variants of ITPKC may have a potential association with HSCR susceptibility and/or developmental diseases related to enteric nervous system development.

KEYWORDS:

Hirschsprung; ITPKC; In silico analysis; Single nucleotide polymorphism (SNP)

PMID:
28664405
DOI:
10.1007/s11033-017-4111-6
[Indexed for MEDLINE]

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