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. It commonly causes joint deformities, disability, and has been associated with major health care costs. In recent years a number of new therapies have become available, with the most efficacious being the anti-TNF agents. Yet, disease remission is rarely achieved. Furthermore, there are no good predictors of clinical response to these agents. Current data indicate that multiple genes underlie the susceptibility to RA, but none of these genes has been definitely identified. The identification of such RA susceptibility and severity genes will not only generate novel and perhaps more specific targets for the development of therapies, but also facilitate early diagnosis and prognostication. 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 are 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 SNP mapping will be done using 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 anti-TNF 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. The GCRC will be central to all three aims, and will be involved in the phenotypic characterization, data and blood collection and sample preparation of families, as well as in the enrollment, drug administration and clinical follow-up in the prospective anti-TNF study. Additionally, the GCRC cores will be utilized for sequencing and SNP ana
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