GENE LINKAGE STUDY OF MULTIPLE SCLEROSIS SIBLING PAIRS

多发性硬化症（MS）是一种以炎症为特征的疾病， 中枢神经系统白色物质脱髓鞘。 MS影响25万人 因此是神经系统残疾的最重要原因， 不包括创伤，发生在早期到中期的成年生活。 间接 有证据表明，免疫系统在发病机制中起作用， MS，来自家庭和双胞胎研究的数据表明，遗传 因素是MS易感性的重要决定因素。 这项研究将试图确定影响基因的身份， 使用受累同胞进行连锁分析，确定MS的易感性 对 （sibpair）方法。 在最初供资期间，70个家庭， 每个人都有2个或更多的兄弟姐妹患有典型的MS， 已识别，并且 预计将有150个家庭接受研究， 项目的进程。 生殖系T细胞受体β的遗传 链（TCR β）基因是相同的血统（IBD）将是 通过分离分析的多态性标记内确定的 TCR β复合体。 类似的研究也将针对那些 编码其它TCR链和主要组织相容性复合体（MHC）。 上位性相互作用，如果它们存在，候选基因之间 将被评估。 TCR β可变区基因的等位基因变体 将通过单链构象研究MS患者遗传的 多态性分析，以评估相关的 基因片段可能是造成同胞间单倍型共享的原因。 在 此外，T细胞对髓磷脂碱性蛋白和蛋白脂质的所有功能 在遗传了MHC和TCR β的同胞中， 这些研究将确定T细胞反应是否 这些髓鞘蛋白与TCR β和MHC的遗传相关 基因IBD或与MS的存在。收集一个大的遗传 作为一个有用的信息库， 可用于MS遗传基础的其他研究的资源 易感性

Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination in central nervous system white matter. MS affects 250,000 American and is thus the most important cause of neurologic disability, excluding trauma, that arises in early to middle adult life. Indirect evidence suggests that the immune system plays a role in the pathogenesis of MS, and data from family and twin studies indicate that genetic factors are important determinants of MS susceptibility. This study will attempt to establish the identity of genes that influence susceptibility to MS by linkage analysis using the affected sibling pair (sibpair) method. During the initial funding period 70 families, each with 2 or more siblings affected with typical MS, have been identified, and it is expected that 150 families will be studied during the course of the project. Inheritance of germline T-cell receptor beta chain (TCRbeta) genes that are identical by descent (IBD) will be determined by segregation analysis of polymorphic markers within the TCRbeta complex. Similar studies will be undertaken for genes that encode other TCR chains and the major histocompatibility complex (MHC). Epistatic interactions, should they be present, between candidate genes will be assessed. Allelic variants of TCRbeta variable region genes inherited by MS patients will be studied by single strand conformation polymorphism analysis in order to assess the possibility that a relevant gene segment may be responsible for haplotype sharing by sibpairs. In addition, the T-cell repertoire to myelin basic protein and proteolipid protein will be identified in siblings who have inherited MHC and TCRbeta genes that are IBD; these studies will define whether the T-cell response to these myelin proteins correlates with inheritance of TCRbeta and MHC genes IBD or with the presence of MS. The collection of a large genetic repository of sibpair MS families should also prove useful as an available resource for other studies of the inherited basis of MS susceptibility.