GENETICS OF INHIBITOR FORMATION IN HEMOPHILIA

血友病A是一种严重的出血性疾病，由于缺乏 凝血因子VIII。约15%至20%的重度 受影响的患者通过替换产生对第VIII因子的抗体 心理治疗。这些抗体被称为抑制物，能中和因子VIII 治疗导致显著的发病率和死亡率。最近的研究 动物模型表明，抑制剂也可能阻碍 基因治疗方法的成功。有几条证据， 包括对血友病兄弟对和动物模型的分析， 表明开发抑制剂的倾向是强烈的 受遗传因素影响，而不是特定的第VIII因子 突变或组织相容性(MHC)基因座类型。这项建议旨在 使用新开发的遗传连锁分析技术和 基因组扫描以确定抑制剂的易感基因。在… 至少200对特征明确的严重血友病一对兄弟 关于缓蚀剂形成的和谐和不和谐，以及其他信息 家庭成员将通过一个合作网络确定 70多个血友病治疗中心的调查人员。样品将会是 和基因组DNA储存库，并伴随着临床和 表征血友病抑制物的流行病学数据库 表型，包括筛选内含子22倒置突变，将 被创造出来。一组候选基因很可能发挥作用 接下来将考察抑制物开发中的积极或消极作用 通过对感兴趣区域中的多态标记进行精细作图， 包括MHC、免疫球蛋白基因、T细胞受体基因和 精选细胞因子和细胞因子受体基因。如果候选基因失效 为了解释对抑制剂开发的遗传易感性，一种 利用大约350个高度多态的基因扫描总共10 cM的基因组 将进行微卫星重复标记。连锁分析将 包括对多个兄弟对进行非参数测试 易感基因和更强大的参数方法 扩展家系中的两种基因模式。新基因组的鉴定 随后将对与抑制剂开发相关的地区进行精细勘探 染色体区域作图和基因克隆技术。DNA 银行和数据库也将是未来唯一有价值的资源 血友病患者的研究。

Hemophilia A is a severe hemorrhagic disorder due to deficiency of coagulation factor VIII. Approximately 15 to 20 percent of severely affected patients develop antibodies to factor VIII with replacement therapy. These antibodies, termed inhibitors, neutralize factor VIII therapy causing significant morbidity and mortality. Recent studies in animal models suggest that inhibitors are also likely to hinder the success of gene therapy approaches. Several lines of evidence, including analyses of hemophilic brother pairs and animal models, indicate that the propensity to develop inhibitors is strongly influenced by genetic factors other than the specific factor VIII mutation or histocompatibility (MHC) locus type. This proposal aims to employ newly developed techniques for genetic linkage analysis and genome scanning to identify the inhibitor susceptibility genes. At least 200 well characterized severe hemophilia A brother pairs, both concordant and discordant for inhibitor formation, and other informative family members will be identified through a collaborative network of investigators in over 70 hemophilia treatment centers. Samples will be collected, and a repository of genomic DNA accompanied by a clinical and epidemiologic data base characterizing the hemophilic inhibitor phenotype including screening for the intron 22 inversion mutation, will be created. A panel of candidate genes that are likely to play a positive or negative role in inhibitor development will then be examined through fine mapping of polymorphic markers in the regions of interest, including the MHC, immunoglobulin genes, the T-cell receptor genes, and selected cytokine and cytokine receptor genes. If candidate genes fail to account for the genetic susceptibility to inhibitor development, a total 10 cM genome scan utilizing approximately 350 highly polymorphic microsatellite repeat markers will be performed. Linkage analysis will include both non-parametric testing of brother pairs for multiple susceptibility genes and more powerful parametric methods for one and two gene models in extended pedigrees. Identification of new genomic regions linked to inhibitor development will then be explored with fine mapping of the chromosomal areas and gene cloning techniques. The DNA bank and database will also be a uniquely valuable resource for future studies of patients with hemophilia.