Abstract
Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses in variable length of the intestine. This study investigated the influence and a possible modifying function of RET proto-oncogene's single nucleotide polymorphisms (SNPs) and haplotypes in the development and phenotype of the disease in Czech patients. Genotyping of 14 SNPs was performed using TaqMan Genotyping Assays and direct sequencing. The frequencies of SNPs and generated haplotypes were statistically evaluated using chi-square test and the association with the risk of HSCR was estimated by odds ratio. SNP analysis revealed significant differences in frequencies of 11 polymorphic RET variants between 162 HSCR patients and 205 unaffected controls. Particularly variant alleles of rs1864410, rs2435357, rs2506004 (intron 1), rs1800858 (exon 2), rs1800861 (exon 13), and rs2565200 (intron 19) were strongly associated with increased risk of HSCR (p<0.00000) and were over-represented in males vs. females. Conversely, variant alleles of rs1800860, rs1799939 and rs1800863 (exons 7, 11, 15) had a protective role. The haploblock comprising variants in intron 1 and exon 2 was constructed. It represented a high risk of HSCR, however, the influence of other variants was also found after pruning from effect of this haploblock. Clustering patients according to genotype status in haploblock revealed a strong co-segregation with several SNPs and pointed out the differences between long and short form of HSCR. This study involved a large number of SNPs along the entire RET proto-oncogene with demonstration of their risk/protective role also in haplotype and diplotype analysis in the Czech population. The influence of some variant alleles on the aggressiveness of the disease and their role in gender manifestation differences was found. These data contribute to worldwide knowledge of the genetics of HSCR.
Highlights
Hirschsprung disease (HSCR) is a congenital developmental malformation characterised by the absence of enteric ganglion cells of myenteric and submucosal plexuses in the intestine
According to the length of the aganglionic segment, the cohort consisted of 117 patients with short-segment HSCR, 41 patients with long-segment aganglionosis, and 4 patients with an unspecified form of HSCR
In single nucleotide polymorphisms (SNPs) rs1864410, rs2435357, rs2506004, rs1800858 the variant allele dominated in HSCR patients and their carriership was associated with more than 6.6-fold elevated risk for development of HSCR compared with the wild-type allele carriership
Summary
Hirschsprung disease (HSCR) is a congenital developmental malformation characterised by the absence of enteric ganglion cells of myenteric and submucosal plexuses in the intestine. The long-segment form of HSCR (L-HSCR) can present as total colonic aganglionosis (TCA) extending from the rectum up to the terminal ileum and, in rare cases, as nearly total bowel (NTBA) or total intestinal aganglionosis (TIA) comprising nearly total or the whole intestine. It occurs as an isolated disorder in 70% of cases, about 12% of cases have a chromosomal abnormality and 18% of cases have additional congenital anomalies [1]
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