Polymorphisms in the genes encoding the 4 RET ligands, GDNF, NTN, ARTN, PSPN, and susceptibility to Hirschsprung disease.
OBJECTIVE
Hirschsprung disease (HSCR) is a developmental disorder caused by a failure of neural crest cells to migrate, proliferate, and/or differentiate during the enteric nervous system development. It presents a multifactorial, nonmendelian pattern of inheritance, with several genes playing some role in its pathogenesis. Its major susceptibility gene is the RET protooncogene, which encodes a receptor tyrosine kinase activating several key signaling pathways in the enteric nervous system development. Given the pivotal role of RET in HSCR, the genes encoding their ligands (GDNF, NRTN, ARTN, and PSPN) are also good candidates for the disease.


METHODS
We have performed a case-control study using Taqman technology to evaluate 10 polymorphisms within these genes, as well as haplotypes comprising them, as susceptibility factors for HSCR.


RESULTS
No differences were found in the allelic frequencies of the variants or in the haplotype distribution between patients and controls. In addition, no particular association was detected of the variants/haplotypes to any demographic/clinical parameters within the group of patients.


CONCLUSIONS
These data would be consistent with the lack of association between these polymorphisms and HSCR, although they do not permit to completely discard a possible role of other variants within these genes in the disease. Moreover, because the gene-by-gene approach does not take into account the polygenic nature of HSCR disease, it would be interesting to investigate sets of variants in many other different susceptibility loci described for HSCR, which may permit to consider possible interactions among susceptibility genes.
Fernandez
Raquel M
RM
Hospitales Universitarios Virgen del Rocio, Spain.
Ruiz-Ferrer
Macarena
M
Lopez-Alonso
Manuel
M
Antiñolo
Guillermo
G
Borrego
Salud
S
D000483:Alleles; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000235:genetics / Q000502:physiology*; D006239:Haplotypes / Q000235:genetics; D006627:Hirschsprung Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D051101:Neurturin / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013030:Spain / Q000453:epidemiology; D000070584:Tripartite Motif Proteins
D004268:DNA-Binding Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051098:Glial Cell Line-Derived Neurotrophic Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; D009687:Nuclear Proteins; C490886:ARTN protein, human; C495039:GDNF protein, human; C495053:NRTN protein, human; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins; C110758:persephin