title: Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease.
abstract: 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.
authors.affiliation: 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.
authors.lastname: Gunadi
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Albee Yun
authors.initials: AY
authors.lastname: Ling
authors.affiliation: Pediatric Surgery Division, Department of Surgery, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia.
authors.lastname: Rochadi
authors.affiliation: Pediatric Surgery Division, Department of Surgery, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia.
authors.forename: Akhmad
authors.initials: A
authors.lastname: Makhmudi
authors.affiliation: Department of Child Health Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta 55281, Indonesia.
authors.forename: Elisabeth Siti
authors.initials: ES
authors.lastname: Herini
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Maria X
authors.initials: MX
authors.lastname: Sosa
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: 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.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D004247:DNA / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006133:Growth Substances; D006627:Hirschsprung Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015994:Incidence; D007214:Indonesia / Q000453:epidemiology; D007438:Introns; D008297:Male; D008934:Mitogens; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D006133:Growth Substances; D008934:Mitogens; C094131:NRG1 protein, human; D020890:Neuregulin-1; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: Common polymorphisms; Genetic interaction; Hirschsprung disease; Indonesian cases