GENETICS OF INHIBITOR FORMATION IN HEMOPHILIA

血友病A是一种严重的出血性疾病， 凝血因子VIII。 大约15%到20%的严重 受影响的患者产生因子VIII抗体， 疗法 这些抗体称为抑制剂， 治疗引起显著的发病率和死亡率。 的近期研究 动物模型表明，抑制剂也可能阻碍 基因治疗方法的成功。 几条证据， 包括对血友病兄弟对和动物模型的分析， 表明形成抑制剂的倾向强烈 受特定因子VIII以外的遗传因素影响 突变或组织相容性（MHC）基因座类型。 这项建议旨在 采用新开发的遗传连锁分析技术， 基因组扫描以鉴定抑制剂易感基因。 在 至少有200对严重血友病A兄弟， 抑制剂形成的一致性和不一致性，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研究人员。 样品将 收集，和一个基因组DNA库伴随着临床和 描述血友病抑制剂特征的流行病学数据库 表型，包括筛选内含子22倒位突变，将 被创造出来。 一组候选基因可能会在基因组中起作用， 然后将检查抑制剂发展中的积极或消极作用 通过在感兴趣的区域中精细定位多态性标记， 包括MHC、免疫球蛋白基因、T细胞受体基因， 选择的细胞因子和细胞因子受体基因。 如果候选基因失败 为了解释对抑制剂形成的遗传易感性， 利用大约350个高度多态性的基因组进行总共10 cM的基因组扫描 将进行微卫星重复标记。 连锁分析将 包括对于多个 易感基因和更强大的参数方法， 两个基因模型的扩展谱系。 新基因组的鉴定 与抑制剂发展相关的区域将被探索， 染色体区域定位和基因克隆技术。 的DNA 银行和数据库也将是未来一个独特的宝贵资源， 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.