Identification of genetic, serum, and clinical factors to allow stratification of patients with early rheumatoidarthritis (RA) according to risk of radiographic severity would improve quality of life for RA patients andbenefit society by substantially lowering morbidity and treatment costs. Genetic influences on radiographicseverity of RA may vary by race/ethnicity, and African-Americans are significantly under-represented in RAresearch studies. Genome-wide gene expression profiling and proteomic techniques have revolutionizedapproaches to identifying markers of disease susceptibility and severity. We hypothesize that a combinationof gene expression patterns in PBMCs, serum protein profiles, and clinical parameters can successfullydistinguish African-Americans with early RA who will develop severe radiographic damage from those whowill not. The NIH-funded CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with EarlyRA) 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. Throughcollaboration with the Autoimmune Biomarkers Collaborative Network (ABCoN), RNA samples suitable forgene expression microarray analyses are currently banked on CLEAR patients. We propose the followingspecific aims: 1. To identify differences in baseline gene expression profiles in PBMCs of African-AmericanRA patients with severe vs. mild radiographic damage at 3 years' disease duration, using microarrays; 2. Toidentify serologic factors influencing radiographic severity of RA in African-Americans by analyzing baselineserum levels of a panel of cytokines, growth factors, and soluble receptors using chip and bead-basedassays; and 3. To determine the relative contributions of clinical, genetic, and serologic factors onradiographic severity of RA in African-Americans using statistical models developed by the MCRC MethologyCore. 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 optimizedfor individual patients, which will significantly improve the clinical care of African-Americans with RA. Inaddition, these studies will provide considerable new insights into the pathogenesis of RA.
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