Garcia-Barceló M M, Miao X, Lui V C H, So M T, Ngan E S W, Leon T Y Y, Lau D K C, Liu T T, Lao X, Guo W, Holden W T, Moore J, Tam P K H
Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine of the University of Hong Kong, Hong Kong SAR, China.
Ann Hum Genet. 2007 Jul;71(Pt 4):526-36. doi: 10.1111/j.1469-1809.2007.00347.x. Epub 2007 Feb 2.
Interactions between migrating neural crest cells and the environment of the gut are crucial for the development of the enteric nervous system (ENS). A key signalling mediator is the RET-receptor-tyrosine-kinase which, when defective, causes Hirschprung's disease (HSCR, colon aganglionosis). RET mutations alone cannot account for the variable HSCR phenotype, invoking interactions with as yet unknown, and probably inter-related, loci involved in ENS development. Homeobox (HOX) genes have a major role in gut development as depicted by the enteric Hox code. We investigated whether DNA alterations in HOX genes, either alone or in combination with RET, are implicated in HSCR. Genotyping effort was minimized by applying the HapMap data on Han Chinese from Beijing (CHB). 194 HSCR patients and 168 controls were genotyped using Sequenom technology for 72 tag, single nucleotide polymorphisms (SNPs) distributed along the HOX clusters. The HapMap frequencies were compared to those in our population and standard statistics were used for frequency comparisons. The multifactor-dimensionality-reduction method was used for multilocus analysis, in which RET promoter SNP genotypes were included. Genetic interactions were found between two HOX loci (5'-HOXA13 and 3'UTR-HOXB7) and the RET loci tested. Minor allele frequencies (MAF) of the SNPs tested in our sample were not significantly different from those reported by HapMap when the sample sizes of the populations compared were considered. This is the first evaluation of the HOX genes in HSCR and the first application of HapMap data in a Chinese population. The interacting HOX loci may affect the penetrance of the RET risk allele. HapMap data for the CHB population correlated well with the general Chinese population.
迁移的神经嵴细胞与肠道环境之间的相互作用对于肠神经系统（ENS）的发育至关重要。一个关键的信号传导介质是RET受体酪氨酸激酶，当其有缺陷时会导致先天性巨结肠（HSCR，结肠神经节缺失症）。仅RET突变不能解释HSCR的可变表型，这引发了与ENS发育中尚未知且可能相互关联的基因座的相互作用。如肠道Hox编码所示，同源框（HOX）基因在肠道发育中起主要作用。我们研究了HOX基因的DNA改变，无论是单独还是与RET联合，是否与HSCR有关。通过应用来自北京汉族（CHB）的HapMap数据，将基因分型工作减到最少。使用Sequenom技术对194例HSCR患者和168例对照进行基因分型，检测沿HOX簇分布的72个标签单核苷酸多态性（SNP）。将HapMap频率与我们人群中的频率进行比较，并使用标准统计方法进行频率比较。采用多因素降维方法进行多位点分析，其中纳入了RET启动子SNP基因型。在两个HOX基因座（5'-HOXA13和3'UTR-HOXB7）与所检测的RET基因座之间发现了基因相互作用。当考虑所比较人群的样本量时，我们样本中所检测SNP的次要等位基因频率（MAF）与HapMap报道的频率无显著差异。这是对HSCR中HOX基因的首次评估，也是HapMap数据在中国人群中的首次应用。相互作用的HOX基因座可能会影响RET风险等位基因的外显率。CHB人群的HapMap数据与一般中国人群相关性良好。
