Diabetes as a Model for Functional Genomics in Multifactorial Diseases

糖尿病和高血压等多因素疾病是由遗传和环境因素复杂相互作用引起的。遗传因素由多个易感基因组成。每个基因对整体表型的影响相对较小，这使得对人类多因素疾病易感基因的识别和功能分析变得困难。为了克服这个问题，我们使用了多因素疾病的近交系动物模型，其中遗传背景是同质的，环境因素很容易控制，并进行了遗传和功能分析，这些模型中产生的信息被应用于人类研究。在1型糖尿病的动物模型NOD小鼠中，MHC连锁易感性(Idd16)的第二个成分已被映射到与II类MHC(Idd1)相邻但不同的区域，并在TNF的启动子区域发现了候选变异，编码细胞因子肿瘤坏死因子。通过祖先单倍型同源基因定位，I12和I121的序列变异被证明是非MHC基因Idd3的有力候选者。在2型糖尿病动物模型NSY小鼠中，三个主要易感基因(Nidd1-3)被定位在第11、14和6号染色体上，产生了拥有每条染色体的共生株，并与对照品系相比，在表型上显示出显著差异，表明我们的策略在复杂性状的遗传解剖方面的能力。

Multifactorial diseases such as diabetes and hypertension are caused by complex interaction of genetic and environmental factors. Genetic factor consists of multiple susceptible genes. The effect of each gene to overall phenotype is relatively small, making the identification and functional analysis of susceptibility genes for multifactorial diseases in humans difficult. To overcome this, we used inbred animal models for multifactorial diseases, in which genetic background is homogeneous and environmental factors can easily be controlled, and genetic and functional analyses were performed, and information generated from studies in these models were applied for human studies.In NOD mice, an animal model for type 1 diabetes, a second component of MHC-linked susceptibility (Idd16) has been mapped to the region adjacent to, but distinct from class II MHC(Idd1), and candidate variants have been identified in promoter region of Tnf, encoding cytokine tumor necrosis factor. By ancestral haplotype congenic mapping, sequence variants in I12 and I121 have been shown to be strong candidates for non-MHC gene, Idd3. In NSY mice, an animal model for type 2 diabetes, three major susceptibility genes (Nidd1-3) have been mapped to chromosomes 11, 14 and 6, consomic strains possessing each of these chromosome have been produced and significant differences in phenotypes as compared with control strain have been shown, indicating the power of our strategy in genetic dissection of complex traits.