CHROMOSOME REGIONS LINKED TO SLE IN MULTIPLEX FAMILIES

与许多多因素复杂的人类疾病相似，SLE成为 临床上表现为当一个人继承了一个临界数量的 易感基因或有足够数量的相互作用 环境因素 然而，这些易感基因仍然存在 难以捉摸。 小鼠1、4、7和17号染色体上的SLE易感性位点是 通过连锁分析在多个近交系中重复鉴定， 狼疮样疾病 它们在人类染色体上的同线位置是 1 q21-q42、1 p22-p36、11 p15或19 q12-q13和6p 21，其中三个是 与人类SLE有关 因此，这些小鼠易感区域 它们的同线人类染色体区域可能含有 重要的致病基因 我们假设1）重要的SLE 易感基因在小鼠和人之间是保守的，和2）如果一个 或者更多的基因座在物种间是保守的，它们可能是保守的， 在几个民族中。 我们现在有非常有希望的初步证据 显示候选1号染色体区域连锁的证据的数据。 我们建议确定这些人类染色体区域 通过连锁和关联研究， SLE多发家系。 为了减少遗传异质性，大多数SLE 患者可分为以自身抗体为特征的临床亚群， es 特异性有限，对有限数量的器官造成损害。 到 完成我们的目标，我们将1）积累300个多元化家庭 包含两个或两个以上SLE一级或二级亲属（强调 收集受影响的同胞对），并将所有个体分类到一个更 具有SLE、GN或 无GN，以及自身抗体（抗dsDNA，Ro，La，Sm， RNP、心磷脂、染色质或ANA）。 2)基因型每个家庭成员 对于位于这些人类染色体区域上的遗传标记，3） 用谱系法鉴定SLE易感基因染色体区域 分析，以及4）定位每个内的主要易感基因 联系区域。 我们的最终目标是找出 增加SLE风险的基因，然后决定这些基因如何 影响免疫反应。

Similar to many multifactorial complex human diseases, SLE becomes clinically manifest when an individual either inherits a critical number of susceptibility genes or has an adequate number which interact with environmental factors. These susceptibility genes, however, remain elusive. SLE susceptibility loci on mouse chromosomes 1,4,7, and 17 were repeatedly identified by linkage analysis in multiple inbred strains prone lupus-like disease. Their syntenic locations on human chromosome are 1q21-q42, 1p22-p36, 11p15 or 19q12-q13, and 6p21, three of which are implicated in human SLE. Therefore, these murine susceptibility regions and their syntenic human chromosomal regions are likely to contain important disease-causing genes. We hypothesize that 1) important SLE susceptibility genes are conserved between mouse and man, and 2) if one or more loci are conserved across species, they are likely to be conserved across several ethnic groups. We now have very promising preliminary data showing evidence of linkage of the candidate chromosome 1 region. We propose to determine whether these human chromosomal regions contain SLE susceptibility genes by both linkage and association studies in SLE multiplex families. To reduce genetic heterogeneity, most SLE patients can be classified into clinical subsets characterized y autoantibo es of restricted specificities and damage to a limited number of organs. To accomplish our goal, we will 1) accumulate 300 multiplex families containing two or more first or second degree relatives with SLE (emphasis on collecting affected sib pairs) and classify all individuals into a more homogeneous population for clinical or laboratory evidence of SLE, GN or no GN, and presence and titers of autoantibodies (to dsDNA, Ro, La, Sm, RNP, cardiolipin, chromatin, or ANA). 2) genotype each family member for genetic markers located on these human chromosomal regions, 3) identify chromosomal regions containing SLE susceptibility genes by linage analysis, and 4) localize the primary susceptibility gene(s) within each linked region by association. Our ultimate goal is to identify individual genes that increase the risk for SLE, then determine how these genes influence immune responses.