The applicant's career goal is to become an independent investigator in the genetics of autoimmune disorders, particularly rheumatoid arthritis (RA). To meet this goal, the applicant proposes a career development plan with emphasis on didactic training in the pathobiology of autoimmunity and hands-on training using state-of-the-art statistical models that can accommodate the unique challenges presented by high dimensional genetic data. A highly accomplished team of investigators with proven track records as mentors will oversee the applicant's career development. The research component of this project strives to discover novel genetic and environmental factors (and their interactions) that determine susceptibility to RA in African Americans. Data and biological samples from African-American RA participants are available from the NIH-funded Consortium for the Longitudinal Evaluation of African- Americans with RA (CLEAR) Registry (~800 RA cases), while those from healthy African- American controls are from the CLEAR Registry (~300 controls) and from the Birmingham, Alabama area (~500 controls). Genotyping data from these ~800 cases and ~800 controls are already available for 9,484 single nucleotide polymorphisms (SNPs) based on the International Major Histocompatibility Complex (MHC) and Autoimmunity Genetics Network (IMAGEN) SNP array. We will perform genotyping of 3 relevant vitamin D receptor gene (VDR) SNPs and measure serum 25(OH)-vitamin D levels on all 1,600 cases and controls. The aims of the study are: 1) To test the hypothesis that the MHC region harbors genes that have effects on RA risk in African Americans independent of HLA DRB1 SE, and to assess the genetic risk of non-HLA candidate loci in the MHC which have known association in populations of European ancestry; 2) to develop a panel of SNPs that be used to impute with high accuracy the HLA-DRB1 alleles associated with RA; and to validate the association of the SE alleles in African Americans with RA; 3) To test the hypothesis that interactions between vitamin D receptor (VDR) SNPs and vitamin D levels will influence the risk of developing RA in African Americans; and 4) To utilize and evaluate the relative performance of the statistical shrinkage methods, penalized regression (LASSO), and Bayesian versions of the LASSO for testing the multiple main effects, gene by gene and gene by environmental interaction effects on RA risk in African Americans. This project will greatly enhance our understanding of the complex genetic and environmental risk factors for RA in a traditionally understudied population and will provide critical training for Dr. Reynolds' development as an independent scientist.