SUSCEPTIBILITY GENES AND BIOMARKERS FOR RHEUMATOID ARTHRITIS (NARAC 2)

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 类风湿关节炎(RA)是一种遗传复杂、临床异质性、病因不明的慢性疾病，约占总人口的0.5-1%。北美类风湿关节炎联盟(NARAC)此前已经确定了几个包含易感基因的基因组区域，这项提议代表着这项工作的继续和扩大，以及识别新的生物标记物来预测结果和临床反应。在具体目标1上，NARAC将确定1,000个“三人”家庭，其中先证者患有血清阳性和侵袭性类风湿关节炎，父母不受影响。将从全国各地的几个地点招募三人组，这对精细绘制包含易感基因的区域至关重要。在特定目标2上，将使用末端脱氧核苷酸转移酶(TDT)对最近在NARAC连锁研究中确定的10个候选染色体区域进行高密度单核苷酸多态(SNP)定位。在缩小感兴趣区域后，候选基因将被重新测序。具体目标3将在一大群RA患者中识别预测抗坏死因子药物治疗反应的生物标记物。患者将接受为期一年的跟踪，并将测试几项参数，包括遗传标记、使用AFFYMENTIAL微阵列在外周血白细胞(PBL)中的基因表达模式、PBL中的细胞表面标记以及几种蛋白质的血清/血浆水平。这些参数将用于比较应答者和非应答者，以确定最佳预测者。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rheumatoid arthritis (RA) is a genetically complex and clinically heterogeneous chronic disease of unknown etiology that affects 0.5-1% of the population. The North American RA Consortium (NARAC) has previously identified several genomic regions containing susceptibility genes, and this proposal represents the continuation and expansion of that work, in addition to the identification of new biomarkers to predict outcome and clinical response. On specific aim 1, the NARAC will identify 1,000 "trio" families, where the proband has seropositive and erosive RA and the parents not affected. Trios will be recruited from several sites around the country and will be critical for the fine mapping of the regions containing susceptibility genes. On specific aim 2, high-density single nucleotide polymorphism (SNP) mapping will be done using terminal deoxynucleotidyl transferase (TDT) in ten candidate chromosomal regions of interest recently identified in the NARAC linkage studies. After narrowing down the regions of interest, candidate genes will be re-sequenced. Specific aim 3 will identify biomarkers predictive for response to therapy with antinecrosis factor agents in a large cohort of RA patients. Patients will be followed for one year and several parameters will be tested, including genetic markers, the pattern of gene expression using Affymetric microarrays in peripheral blood leucocytes (PBL), cell surface markers in PBL, and serum/plasma levels of several proteins. These parameters will be used to compare responders and non-responders in order to identify the best predictors.