Analysis for molecular-pathogenesis of Hirschsprung disease. As a model of multifactorial disease

[背景]随着人类基因组计划的快速推进，人们对单纯性孟德尔遗传病的遗传缺陷有了更多的认识。但单纯性孟德尔遗传病是罕见病，占新生儿的1.25%。现在我们的兴趣转向普通疾病。多因素疾病的发生受遗传基础和环境状况的影响。现在我们还没有工具来理解这些复杂的现象。简单的方案是必要的了解多因素疾病。[研究对象与方法]先天性巨结肠是小儿常见的消化道疾病，其发病机制与环境因素无关。证据为1/5000，男性占优势。该病发病率较高，属遗传性疾病，无环境因素。先天性巨结肠是一个很好的候选人简单的多基因疾病。迄今为止，广泛的突变分析的候选基因的先天性巨结肠病，只有50%的患者被确定致病突变。我们认为该疾病在候选基因（EDN 3、EDNRB、SOX 10和GDNF）之间发生了基因和基因的相互作用。我们采用RET基因突变分析和基于单体型的病例对照研究相结合的方法。[结果] 34例散发性病例中5例RET基因突变，1例家族性病例RET基因突变。基于单倍型的病例对照研究表明，特定的单倍型与疾病之间没有关系。

[Background] Rapid proceeding of human genome project, we got many knowledge for genetic defects of simple mendelian diseases. But simple mendelian diseases were rare diseases ; frequency was 1.25% of born infants. Now our interest goes toward common disease. Multifactorial disease occurs under influence of genetic basis and environmental status. Now we do not have a tool to understand these complicated phenomena. Simple scheme was necessary to understand multifactorial disease. Now we choose the Hirschsprung disease as model of multigenetic disease without environmental factors[Subjects and method] Hirschsprung disease is a common digestive disease in young children. Evidence was 1/5000 and predominance in male. The disease has relatively high incidence and is genetic disease without environmental factors. Hirschsprung disease is a good candidate for simple multigenetic disease. To date, extensive mutational analysis of candidate genes of Hirsch sprung disease, only 50% of patients were identified disease causative mutation. We think this disease has occurred gene and gene interactions among candidate genes (EDN3,EDNRB, SOX10 and GDNF). We applied two-combined approach, RET gene mutational analysis and haplotype based case control study.[Results] We found RET mutation in 5 cases (total 34 sporadic cases) and 1 familial case. Haplotype based case control study showed no relationship between specific haploype and disease.