RET polymorphisms and the risk of Hirschsprung’s disease in a Chinese population

Abstract

Hirschsprung's disease (HSCR) is a congenital disorder characterized by intestinal obstructions due to the absence of enteric ganglia along variable lengths of the intestinal tract. RET coding mutations have been found in approximately 50% of familial cases, but they only explain a minority of sporadic cases. Here, we report our investigation of a possible role of RET non-coding mutations in sporadic HSCR patients. The haplotypes of seven single nucleotide polymorphisms (SNPs), all located in a region 4 kb upstream of the gene through to 23 kb of intron 1, and one SNP in exon 2 were constructed in 125 Han Chinese patients with sporadic HSCR and in 148 Han Chinese controls. Our results indicated that eight SNPs were significantly associated with HSCR (P \ 0.0001). The C allele of rs2505535 would appear to represent a protecting allele for the Chinese population. One single haplotype composed of these eight markers was present in 59.6% of patients, versus 18.1% of controls. Based on our results, we conclude that non-coding mutations in RET have important roles in the development of HSCR. The unknown functional disease variant(s), with a dosage-dependent effect in HSCR, is likely to be located in the 5 0 -region of the RET gene.

Genetic variants in RET and risk of Hirschsprung's disease in Southeastern Chinese: a haplotype-based analysis

“…Liu CP et al reported C135 G/A and C1296 A/G at exon 2 and the combination of AG of these two SNPs were associated with susceptibility of HSCR in Southeast Chinese population [17,18]. Also, they observed these two SNPs were in LD with two other coding SNPs at exon 14 and exon 15 in the same population.…”

Potential association of VAMP5 polymorphisms with total colonic aganglionosis in Hirschsprung disease

“…Recently, a genome‐wide association study (GWAS) has revealed that a new candidate gene of NRG1 is associated with the risk of HSCR . Genetic associations of the single nucleotide polymorphisms (SNPs) in known susceptibility genes (such as rs2435357 and rs2505535 in RET , and rs2439305 in NRG1 ) were replicated in a number of studies . More recently, in our prior GWAS in a Korean population to discover new genetic loci in HSCR, vesicle‐associated membrane protein 5 ( VAMP5 ) was identified as a potential risk factor for the TCA subgroup of HSCR patients with a significance of p = 8.03 × 10 −5 at rs1254900 …”

“…9 Genetic associations of the single nucleotide polymorphisms (SNPs) in known susceptibility genes (such as rs2435357 and rs2505535 in RET, and rs2439305 in NRG1) were replicated in a number of studies. [10][11][12][13] More recently, in our prior GWAS in a Korean population to discover new genetic loci in HSCR, vesicle-associated membrane protein 5 (VAMP5) was identified as a potential risk factor for the TCA subgroup of HSCR patients with a significance of p = 8.03 9 10 À5 at rs1254900. 14 VAMP5 encodes synaptobrevin (a member of the SNARE protein complex), and its family has been reported to participate in the synaptic vesicle fusion process of ENS neurotransmission.…”

Advances in Molecular Genetics of Hirschsprung's Disease

“…The risk of heterozygous haploid in developing HSCR was 2 times higher than the normal population and 20 times higher than the homozygous haploid. In our analysis of the RET intron in the Chinese population with HSCR, we found that a high transmission frequency of the RET +3: T allele led to an increased susceptibility to HSCR (Zhang et al, 2007; Liu et al, 2008). A 5.7‐fold and 2.1‐fold increase in susceptibility to HSCR in males and females, respectively, was estimated in SNP haplotypes of the RET +3.…”

“…We also found that the distribution of some other polymorphisms in the intron 1 was significantly different between cases and controls. Among these, two haplotypes were significantly associated with HSCR (Liu et al, 2008). Emison et al studied 882 probands with HSCR and 1478 first‐degree relatives from the US, European, and Chinese families and found that common mutations, individually and together, may contribute to the risk of HSCR.…”