Bennett S T, Todd J A
Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, United Kingdom.
Annu Rev Genet. 1996;30:343-70. doi: 10.1146/annurev.genet.30.1.343.
We review the strategy used to identify a susceptibility locus (IDDM2) for type 1 (insulin dependent) diabetes mellitus. As type 1 diabetes is becoming the paradigm for dissecting multifactorial disease genetics, the approach described provides important general guidelines for positional cloning of human disease polygenes. Main topics include: (a) historical conspectus of the mapping and identification of IDDM2--a critical survey of the work leading up to the conclusion that IDDM2 most likely corresponds to allelic variation at the insulin gene minisatellite (VNTR) locus; (b) the nature of allelic (length and sequence) variation at the VNTR locus; (c) gene interactions and disease pathogenesis; (d) mechanism of action of the INS VNTR in type 1 diabetes--insulin gene expression, parent-of-origin effects (genomic imprinting); and (e) summary and future prospects--alleles of the insulin VNTR that are protective for type 1 diabetes appear to encode susceptibility to type 2 diabetes.
我们回顾了用于鉴定1型（胰岛素依赖型）糖尿病易感性位点（IDDM2）的策略。由于1型糖尿病正成为剖析多因素疾病遗传学的范例，所描述的方法为人类疾病多基因的定位克隆提供了重要的通用指南。主要主题包括：（a）IDDM2定位与鉴定的历史概述——对得出IDDM2最有可能对应胰岛素基因小卫星（VNTR）位点等位基因变异这一结论的前期工作的批判性审视；（b）VNTR位点等位基因（长度和序列）变异的性质；（c）基因相互作用与疾病发病机制；（d）INS VNTR在1型糖尿病中的作用机制——胰岛素基因表达、亲本来源效应（基因组印记）；以及（e）总结与未来展望——对1型糖尿病具有保护作用的胰岛素VNTR等位基因似乎编码对2型糖尿病的易感性。
