SUSCEPTIBILITY GENES AND BIOMARKERS FOR RHEUMATOID ARTHRITIS (NARAC 2)

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 风湿性关节炎（RA）是一种遗传复杂且临床异质性的慢性疾病，病因不明，影响0.5-1%的人群。北美RA联盟（NARAC）以前已经确定了几个含有易感基因的基因组区域，除了确定新的生物标志物来预测结果和临床反应外，这项建议代表了这项工作的继续和扩展。在具体目标1方面，NARAC将确定1，000个“三人”家庭，即先证者血清反应阳性和糜烂性类风湿关节炎，而父母不受影响。将从全国各地的几个地点招募三人组，这对含有易感基因的区域的精细定位至关重要。在具体目标2中，将使用末端脱氧核苷酸/转移酶（TDT）在NARAC连锁研究中最近确定的10个候选染色体区域中进行高密度单核苷酸多态性（SNP）作图。在缩小感兴趣的区域后，候选基因将被重新测序。具体目标3将在一个大型RA患者队列中确定预测抗坏死因子药物治疗反应的生物标志物。将对患者进行为期一年的随访，并将检测几个参数，包括遗传标志物、使用Affymetric微阵列检测外周血白细胞（PBL）中的基因表达模式、PBL中的细胞表面标志物和几种蛋白质的血清/血浆水平。这些参数将用于比较应答者和非应答者，以确定最佳预测因子。

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 deoxynucleotide/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.