GENETIC ANALYSIS OF RHEUMATOID ARTHRITIS SIBLING PAIRS

类风湿性关节炎的原因尚不清楚，而 主要组织相容性复合体以外的遗传因素的重要性 6号染色体上的(MHC)不明显。北美类风湿 关节炎联盟(NARAC)已经成立，以全面解决 这个问题使用了各种策略，包括受影响的同胞对 分析和传输不平衡测试。该财团由 在十个合作中心中，将建立一个协调的国家 努力识别和收集800对受影响的类风湿兄弟姐妹 关节炎。明确定义的与RA的兄弟姐妹对将由八人收集 在十个合作中心中。是否进入这项研究将取决于 标准化标准，事实证明面对临床评估 每一对手部X光片由一名放射科医生读取，并集中 血清学检测。在可能的情况下，父母和未受影响的兄弟姐妹将 被收集起来。一个集中的临床数据库、DNA、血清和细胞库 将为所有受影响的兄弟姐妹和家庭成员建立。 该联盟将利用等位基因方法进行全基因组筛查，以 确定MHC外的基因区域是否与 易患类风湿性关节炎。将进行候选基因区域的筛选 通过使用一组高度多态的 微卫星标记以10-15 cM的间隔横跨整个 人类基因组。较大的样本量应该可以用于分析 具有高遗传表型的同胞对的特定亚群 风险，即早发性疾病和男性。当候选区域为 ，该财团将通过以下方式进一步分析这些地区 基于关联的方法，包括传输不平衡测试 在感兴趣的遗传区域中具有稀疏间隔的标记。这个 该财团预计将确定5至10个感兴趣的候选地区。通过 利用这些区域的紧密分布的多态标记，该联盟 期望能够定义单倍型，可以对其进行测试 传播途径与类风湿关节炎疾病易感性的关系 不平衡检验。 在UAB，我们建议识别并收集拟议的800个兄弟姐妹中的200个 成对的。我们还将对所有患者进行人类白细胞抗原寡核苷酸分型 已确认身份。尽管这项多中心研究对所有患者开放 种族群体，在UAB将重点放在收集 非裔美国人的起源，因为这个民族的频率相对较低 其他协作中心所服务的人群中的一组。

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 question 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 fact to face clinical evaluation of every sib pair, hand x-rays read by a single radiologist, and centralized serological testing. Where possible, 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 susceptiblity 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 losely 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 expects to be able to define haplotypes tha can be tested for their association with disease susceptibility for RA by transmission disequilibrium testing. At UAB we propose to identify and collect 200 of the proposed 800 siblings pairs. We will also perform HLA oligotyping of all of the patients identified. Although the multicenter study is open to patients from all ethnic groups, at UAB emphasis will be placed on collecting families of African-American origin due to the relatively low frequency of this ethnic group in the populations served by the other collaborating centers.