TY - JOUR
T1 - Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease
AU - Gunadi,
AU - Kapoor, Ashish
AU - Ling, Albee Yun
AU - Rochadi,
AU - Makhmudi, Akhmad
AU - Herini, Elisabeth Siti
AU - Sosa, Maria X.
AU - Chatterjee, Sumantra
AU - Chakravarti, Aravinda
N1 - Funding Information:
We wish to thank the numerous patients and their families who have participated in these studies and the members of our staff and laboratories who have contributed to their ascertainment and for discussions. We are also grateful to Courtney Berrios for IRB management. The studies reported here were supported by the following grants: USA: National Institutes of Health (MERIT Award HD28088 to A.C.) and Indonesia: Ministry of Education and Culture ( DIKTI-FULBRIGHT Senior Research Program 2012 to G.).
Publisher Copyright:
© 2014 Elsevier Inc.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
KW - Common polymorphisms
KW - Genetic interaction
KW - Hirschsprung disease
KW - Indonesian cases
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U2 - 10.1016/j.jpedsurg.2014.04.011
DO - 10.1016/j.jpedsurg.2014.04.011
M3 - Article
C2 - 25475805
AN - SCOPUS:84919430145
VL - 49
SP - 1614
EP - 1618
JO - Journal of Pediatric Surgery
JF - Journal of Pediatric Surgery
SN - 0022-3468
IS - 11
ER -