GENETIC ANALYSIS OF RHEUMATOID ARTHRITIS SIBLING PAIRS

类风湿性关节炎的病因尚不清楚，6号染色体上主要组织相容性复合体(MHC)以外的遗传因素的数量和重要性也是未知的。北美类风湿性关节炎联合会(NARAC)已经成立，以综合解决这一问题，采用各种策略，包括受影响的同胞对分析和传递不平衡测试。该联盟由10个合作中心组成，它们将在全国范围内开展协调一致的工作，以识别和收集800对受影响的类风湿性关节炎兄弟姐妹。十个合作中心中的八个将收集与RA明确定义的兄弟姐妹对。进入这项研究将取决于标准化标准，通过对每对同胞进行面对面的临床评估，由一名放射科医生读取手部X光，以及集中的血清学测试来记录。在可能的情况下，将收集有关父母和未受影响的兄弟姐妹的数据。将为所有受影响的兄弟姐妹和家庭成员建立一个集中的临床数据库、DNA、血清和细胞库。该联盟将利用等位基因方法进行全基因组筛查，以确定MHC以外的遗传区是否与RA的易感性有关。候选遗传区域的筛选将通过分析等位基因共享来完成，方法是使用一组在整个人类基因组中以10-15厘米间隔分布的高度多态的微卫星标记。大样本量应该允许分析具有高遗传风险的表型的同胞对的特定亚组，即早发性疾病和男性。当确定候选区域时，该联盟将通过基于关联的方法进一步分析这些区域，包括在感兴趣的遗传区域中使用紧密间隔的标记进行传递不平衡测试。该财团预计将确定5至10个感兴趣的候选地区。通过在这些区域使用紧密分布的多态标记，该联盟预计能够定义单倍型，这些单倍型可以通过传递不平衡测试来测试它们与RA疾病易感性的关联。

The cause of rheumatoid arthritis is unknown, and the number and importance of genetic factors outside the Major Histocompatibility Complex (MHC) on chromosome 6 are obscure. The North American Rheumatoid Arthritis Consortium (NARAC) has been formed to comprehensively address this questions using a variety of strategies including affected sib pair analysis and transmission disequilibrium testing. The consortium consists of ten collaborating centers which will mount a coordinated national effort to identify and collect 800 affected sibling pairs with rheumatoid arthritis. Well-defined sibling pairs with RA will be collected by eight of the ten cooperating centers. Entry into the study will depend on standardized criteria, documented by face to face clinical evaluation of every sib pair, hand X-rays read by a single radiologist, and centralized serological testing. Where possible, data on parents and unaffected siblings will be collected. A centralized clinical database, DNA, serum and cell bank will be established for all affected sibling pairs and family members. The consortium will utilize allele methods for genome wide screening to establish whether genetic regions outside the MHC are linked to susceptibility to RA. Screening for candidate genetic regions will be done by an analysis of allele sharing using a panel of highly polymorphic microsatellite markers spaced at 10-15 cM intervals across the entire human genome. The large sample size should allow for the analysis of specific subgroups of sib pairs with phenotypes indicative of high genetic risk, namely early onset disease and male sex. When candidate regions are identified, the consortium will further analyze these regions by association based methods, including transmission disequilibrium testing with closely spaced markers in the genetic regions of interest. The consortium expects to identify 5 to 10 candidate regions of interest. By using closely spaced polymorphic markers in these regions, the consortium expcets to be able to define haplotypes that can be tested for their association with disease susceptibility for RA by transmission disequilbrium testing.