Potential association between ITPKC genetic variations and Hirschsprung disease

Jeong Hyun Kim, Soo Min Jung, Joong Gon Shin, Hyun Sub Cheong, Jeong Meen Seo, Dae Yeon Kim, Jung Tak Oh, Hyun-Young Kim, Kyuwhan Jung, Hyoung Doo Shin

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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 P = 0.004) and a haplotype (P = 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.

Original languageEnglish
Pages (from-to)307-313
Number of pages7
JournalMolecular Biology Reports
Issue number3
StatePublished - 1 Jul 2017


  • Hirschsprung
  • In silico analysis
  • Single nucleotide polymorphism (SNP)

Cite this

Kim, J. H., Jung, S. M., Shin, J. G., Cheong, H. S., Seo, J. M., Kim, D. Y., Oh, J. T., Kim, H-Y., Jung, K., & Shin, H. D. (2017). Potential association between ITPKC genetic variations and Hirschsprung disease. Molecular Biology Reports, 44(3), 307-313. https://doi.org/10.1007/s11033-017-4111-6