Diabetes as a Model for Functional Genomics in Multifactorial Diseases

糖尿病、高血压等多因素疾病是遗传和环境因素复杂相互作用的结果。遗传因子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，这使得人类多因子疾病易感基因的鉴定和功能分析变得困难。为了克服这一点，我们使用遗传背景同质且环境因素易于控制的多因子疾病的近交系动物模型，进行遗传和功能分析，并将这些模型研究产生的信息应用于人类研究。在NOD小鼠（一种1型糖尿病动物模型）中，MHC相关易感性的第二个成分（Idd16）已被定位到与II类MHC（Idd1）相邻但不同的区域，并且在编码细胞因子肿瘤坏死因子的Tnf启动子区域鉴定了候选变体。通过祖先单倍型同源定位，I12和I121序列变异已被证明是非mhc基因Idd3的强候选基因。在2型糖尿病动物模型NSY小鼠中，三个主要易感基因（Nidd1-3）被定位到染色体11,14和6上，已经产生了具有这些染色体的经济菌株，并且与对照菌株相比，表型存在显着差异，这表明我们的策略在复杂性状的遗传解剖中具有强大的力量。

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.