GENETIC ANALYSIS OF RHEUMATOID ARTHRITIS SIBLING PAIRS

类风湿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尚不清楚。北美类风湿关节炎联盟（NARAC）的成立是为了全面解决这一问题，使用多种策略，包括受影响的兄弟姐妹对分析和传播不平衡测试。该联盟由十个合作中心组成，它们将发起一项全国性的协调努力，以确定和收集800对患有类风湿性关节炎的兄弟姐妹。10个合作中心中的8个将收集具有RA的明确的兄弟姐妹配对。进入研究将取决于标准化的标准，通过对每一对兄弟姐妹进行面对面的临床评估，由一名放射科医生阅读的手部x光片和集中的血清学检测来记录。在可能的情况下，收集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选，以确定MHC外的遗传区域是否与RA易感性相关。候选遗传区域的筛选将通过在整个人类基因组中间隔10-15 cM的高度多态微卫星标记进行等位基因共享分析来完成。大样本量应该允许分析具有高遗传风险表型的兄弟姐妹对的特定亚群，即早发性疾病和男性。当候选区域被确定后，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。该联盟预计将确定5至10个感兴趣的候选区域。通过在这些区域使用紧密间隔的多态性标记，该联盟希望能够定义单倍型，通过传播不平衡测试来测试它们与类风湿关节炎疾病易感性的关联。

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.