Identification of genetic, serum, and clinical factors to allow stratification of patients with early rheumatoid arthritis (RA) according to risk of radiographic severity would improve quality of life for RA patients and benefit society by substantially lowering morbidity and treatment costs. Genetic influences on radiographic severity of RA may vary by race/ethnicity, and African-Americans are significantly under-represented in RA research studies. Genome-wide gene expression profiling and proteomic techniques have revolutionized approaches to identifying markers of disease susceptibility and severity. We hypothesize that a combination of gene expression patterns in PBMCs, serum protein profiles, and clinical parameters can successfully distinguish African-Americans with early RA who will develop severe radiographic damage from those who will not. The NIH-funded CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early RA) Registry is a unique multi-center, prospective, longitudinal study in which comprehensive demographic, socioeconomic, clinical, and serial radiographic data, as well as DNA and serum, are available. Through collaboration with the Autoimmune Biomarkers Collaborative Network (ABCoN), RNA samples suitable for gene expression microarray analyses are currently banked on CLEAR patients. We propose the following specific aims: 1. To identify differences in baseline gene expression profiles in PBMCs of African-American RA patients with severe vs. mild radiographic damage at 3 years'disease duration, using microarrays;2. To identify serologic factors influencing radiographic severity of RA in African-Americans by analyzing baseline serum levels of a panel of cytokines, growth factors, and soluble receptors using chip and bead-based assays;and 3. To determine the relative contributions of clinical, genetic, and serologic factors on radiographic severity of RA in African-Americans using statistical models developed by the MCRC Methology Core. The ultimate goal of this proposal is to translate insights from clinical rheumatology, biotechnology, and statistical genetics into clinically useful tests to predict radiographic severity of RA in African-Americans. When robust, reliable markers of radiographic severity are established, treatment stategies can be optimized for individual patients, which will significantly improve the clinical care of African-Americans with RA. In addition, these studies will provide considerable new insights into the pathogenesis of RA.
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