Julier C, Lucassen A, Villedieu P, Delepine M, Levy-Marchal C, Danzé P M, Bianchi F, Boitard C, Froguel P, Bell J
INSERM U358, Hôpital Robert Debré, Paris.
Am J Hum Genet. 1994 Dec;55(6):1247-54.
Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.
关联研究和连锁研究表明，胰岛素依赖型糖尿病（IDDM）易感性所涉及的遗传因素中，至少有一个包含在胰岛素基因的一个4.1kb区域内。序列分析已在该区域鉴定出10个与IDDM风险增加相关的DNA变异体。这些变异体彼此处于强连锁不平衡状态，先前的研究未能区分导致IDDM易感性增加的变异体和由于连锁不平衡而与该疾病相关的其他变异体。为了解决这个问题，我们对法国糖尿病患者和对照人群进行了大规模研究，并同时分析了几个变异位点的基因型模式。这导致鉴定出一个由四个变异体（-2733AC、-23HphI、-365VNTR和+1140AC）组成的子集，其中至少有一个似乎直接与疾病易感性有关。本文应用于识别IDDM潜在易感性变异体问题的多DNA变异体关联分析方法，在许多其他多因素疾病的研究中可能很重要。
