Background Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients.
Methods Sixty isolated HSCR patients and 124 controls were ascertained for this study. The three genetic markers were examined using TaqMan Genotyping Assays in genomic DNA for association studies.
Results RET rs2435357 showed the strongest association with HSCR both by case-control analysis (p = 2.5 × 10-8) and transmission disequilibrium test (p = 4.2 × 10-6). NRG1 rs7835688 was modestly associated with HSCR only by case-control analysis (p = 4.3 × 10-3), whereas rs16879552 demonstrated no association (p > 0.097). Two locus analyses of variants showed significant interactions with increased and decreased disease risks of HSCR at NRG1 but conditional on rs2435357 genotype.
Conclusions RET and NRG1 variants are common susceptibility factors for HSCR in Indonesia. These common variants demonstrate that development of HSCR requires joint effects of RET and NRG1 early in gut development.
- Common polymorphisms
- Genetic interaction
- Hirschsprung disease
- Indonesian cases
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health