GENETIC LINKAGE IN LUPUS

这个项目集中于系统性狼疮的免疫遗传学 红斑 初步观察到MB1和MB2的杂合子 (now DQ 1和DQ 2）与抗Ro自身抗体的产生有关 在干燥综合征（54），现在已经扩展到并符合 系统性红斑狼疮（55，56）。 基因互补一直是 通过分析建立了这种关系的遗传基础， DQA1和DQB1基因的限制性片段长度多态性（8）。 的 最近在DNA序列水平上使用DQ寡聚分型的分析 显示了相关的DQ 1等位基因（DQ 1A *0101、*0102和 *0103）的总和 有助于这种基因互补效应， DQB 1 *0201。 此外，T细胞受体等位基因，它们本身是 与反Ro生产相关，与DQ合作 产生抗Ro自身抗体的等位基因。 其他免疫遗传学研究 也被执行。 而不是追求分子间的相互作用， DQ和T细胞受体等位基因与抗Ro自身抗体， 调查人员已经选择追求更基本信息，有关 遗传起源的狼疮通过启动连锁研究。 近期 高度多态性短核苷酸重复序列的发现和作图 人类基因组DNA使得在狼疮中进行连锁研究变得可行， 考虑到狼疮的遗传复杂性 理论工作 已经进行了一年多，最终发展成一个 实际的实验计划。 我们最近的努力集中在 积累多重家系并启动等位基因 与新可用的标记基因座的分配。 200个DNA引物 (105我们拥有的）从这些多态的选择 可利用确定的和作图的基因座的标记来分配等位基因 与候选基因有关。 在即将到来的供资周期中， 研究者建议评估狼疮多重家系连锁 在三个层面：首先是自身免疫血清学，其次是临床 分类（即诊断）的狼疮，和第三与狼疮的特征。 发现与自身免疫血清学的联系预计需要最少的 多重谱系和最少的努力。 随后，数据库 将扩展到定义与狼疮的联系，并最终 特殊的临床表现和实验室检查结果。 实质性 已经取得了进展，有足够的权力， 已经收集的家谱预测，发现遗传连锁， 可能是自身抗体 血统书的收集将继续下去， 这种联系可以用狼疮的诊断和表现来定义， 继续采用现有的应计程序。 如果是全身性 红斑狼疮是以往任何时候都要了解，那么无论是遗传和 使这种疾病有可能发生的环境特征 必须被识别。 这项寻求联系的研究是关键的第一步， 定义狼疮产生和持续的遗传环境。

This project has concentrated upon the immunogenetics of systemic lupus erythematosus. The original observation that heterozygotes of MB1 and MB2 (now DQ1 and DQ2) are related to the production of anti-Ro autoantibodies in Sjogren's Syndrome (54) has now been extended to and conformed in systemic lupus erythematosus (55,56). Gene complementation has been established as the genetic basis for this relationship by analysis of restriction fragment length polymorphisms of DQA1 and DQB1 genes (8). The most recent analysis at the DNA sequence level using DQ oligotyping has shown the related DQ1 allels (DQ1A*0101, *0102 and *0103) in aggregate contribute to this gene complementation effect in combination with DQB1*0201. Moreover, T cell receptor alleles, which themselves are associated to anti-Ro production, act in a cooperative fashion with the DQ alleles for anti-Ro autoantibody production. Other immunogenetic studies have also been performed. Rather than pursuing molecular interactions that govern the association of DQ and T cell receptor alleles with anti-Ro autoantibodies, the investigators have elected to pursue more basic informatin concerning the genetic origins of lupus by initiating a linkage study. The recent discovery and mapping of highly polymorphic short nucleotide repeats in genomic human DNA has made a linkage study feasible in lupus, even considering the genetic complexities that lupus poses. Theoretical work has been underway for over a year, culminating in the development of a practical experimental plan. Our more recent efforts have focused upon accruing multiplex pedigrees and initiating the process of allele assignment with the newly available marker loci. Two hundred DNA primers (105 of which are in our possession) from a selection of these polymorphic markers of defined and mapped loci are available by which to assign alleles linked to candidate genes. For the coming cycle of funding the investigator proposes to evaluate linkage in multiplex pedigrees fro lupus at three levels: first with autoimmune serology, second with the clinical classification (i.e. diagnosis) of lupus, and third with features of lupus. Finding linkage to autoimmune serology is predicted to require the fewest multiplex pedigrees and least effort. Subsequently, the data base developed will be extended to define linkage to lupus and finally to particular clinical manifestations and laboratory findings. Substantial progress has already been made and there is sufficient power in the pedigrees already collected to predict that finding genetic linkage to autoantibodies is likely. The collection of pedigrees will continue so that linkage can be defined with the diagnosis and manifestations of lupus with the continuation of the accrual procedures now in place. If systemic lupus erythematosus is ever to be understood, then both the genetic and environmental features which make it possible for this disease to occur must be identified. This study seeking linkage is a critical first step in defining the genetic environment in which lupus arises and is sustained.