Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease.
Ashish Kapoor, Albee Yun Ling, Akhmad Makhmudi, Elisabeth Siti Herini, Maria X Sosa, Sumantra Chatterjee, Aravinda Chakravarti
Author Information
Gunadi: Pediatric Surgery Division, Department of Surgery, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia; Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ashish Kapoor: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Albee Yun Ling: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Rochadi: Pediatric Surgery Division, Department of Surgery, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia.
Akhmad Makhmudi: Pediatric Surgery Division, Department of Surgery, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia.
Elisabeth Siti Herini: Department of Child Health Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia.
Maria X Sosa: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sumantra Chatterjee: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Aravinda Chakravarti: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: aravinda@jhmi.edu.
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.
