Rheumatoid arthritis (RA) is a chronic, disabling illness of unknown cause. Although both genetic and non-genetic factors are clearly important in disease onset and progression, little is known about specific risk factors. Furthermore, interactions among genetic and non-genetic factors are likely to be important, yet this remains an underexplored area of investigation. Substantial evidence implicates the Major Histocompatibility Complex (MHC) region in RA susceptibility. However, existing studies fail to define precisely which of the numerous candidate genes in this region influence disease risk, and whether they have independent or interactive effects. Specifically, strong evidence supports a role for the HLA-DRB1 """"""""shared epitope,"""""""" however, there is strong evidence that other MHC region loci likely influence RA risk or severity. Non-MHC genes must also be important, yet little is known about other genetic risk factors. Preliminary data by our group and others suggest a role for T cell receptor B (TCRB) genes in RA susceptibility. Finally, although non-genetic factors are estimated to explain at least 50% of RA risk, little is known about specific non-genetic risk factors. In this study, we will focus on two gene regions and two categories of non-genetic factors that are implicated in RA etiology based on pathophysiologic considerations and previous genetic and epidemiologic studies. Specifically, we will examine four candidates within or near the MHC region (HLA-DRB1, -DMA, tumor necrosis factor exposure to cigarette smoke. Our analysis will explicitly assess the presence of independent and interactive effects upon certain patient and disease characteristics. Our choice of analytic method, the transmission disequilibrium test, will allow us to study an ethnically diverse sample while maintaining false positive associations arising from population admixture. The results of this study will: 1) more precisely define the MHC contribution to RA; 2) evaluate the role of the TCRB gene complex; 3) provide new and important information about discrete non-genetic risk factors in RA onset and disease expression; and 5) provide important information about potential sources of genetic heterogeneity that will inform the design and analysis of future genetic epidemiologic studies of RA.
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