The shared epitope (SE) hypothesis was initially proposed to explain genetic susceptibility to rheumatoid arthritis (RA), but further study suggests that the primary role of the SE may be in the development of more severe manifestations of the disease. Despite numerous studies over the past decade, the true relationship of the SE and RA severity remains unclear. Difficulty in clarifying this relationship is likely due to differences in the populations studied: those of ethnicity, clinical factors and the particular SE allele inherited as well as the small number of patients in individual studies. In order to examine the association thoroughly, evaluation of a large, clinically and ethnically diverse population is required, and to date, no attempt has been made to initiate such a project. The goal of this proposal is to precisely define the role of the SE in severity of RA among patients with a broad range of ethnic and clinical characteristics. In order to accomplish this goal we have the following specific aim for this project: 1. To perform a meta-analysis of the association of the SE and severity of RA utilizing individual level data obtained from researchers worldwide. Because the relationship between genotype and RA severity appears to vary according to characteristics of the patients, such as ethnicity and gender, the importance of these covariates will be examined. The association will be analyzed in terms of three genetic models: presence or absence of the SE, SE dosage (0, 1, or 2 alleles), and by the specific SE genotype inherited. Severity of RA will be defined by the following outcome measures: seropositivity, presence of radiographic erosions, disease course, requirement for joint surgery, and presence of nodules or other extra- articular manifestations. This proposal of a meta-analysis with use of individual level data will allow us to more clearly define the precise relationship between the SE and RA severity and has the ability to provide genetic predictors of prognosis for RA patients.
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