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.
Rheumatoid arthritis is an autoimmune disease of unknown cause, but both genetics and environmental factors appear to play a role. There are racial/ethnic differences in the genetics underlying the disease. In this application, we will seek to discover novel genetic and environmental factors and their interactions that contribute to RA in African Americans, a minority group that has been underrepresented in RA research. With this knowledge we will begin to detail individual and population based predictors of the development of RA which may have an impact on the diagnosis and treatment of RA in African Americans.
|Ferraz-Amaro, Iván; Winchester, Robert; Gregersen, Peter K et al. (2017) Coronary Artery Calcification and Rheumatoid Arthritis: Lack of Relationship to Risk Alleles for Coronary Artery Disease in the General Population. Arthritis Rheumatol 69:529-541|
|Wang, Yuge; Hwangpo, Tracy; Martin, Maureen P et al. (2016) Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis. J Allergy Clin Immunol 138:1495-1498|
|Reynolds, Richard J; Vazquez, Ana I; Srinivasasainagendra, Vinodh et al. (2016) Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index. Rheumatol Int 36:263-70|
|Navarro-Millán, Iris; Darrah, Erika; Westfall, Andrew O et al. (2016) Association of anti-peptidyl arginine deiminase antibodies with radiographic severity of rheumatoid arthritis in African Americans. Arthritis Res Ther 18:241|
|Reynolds, Richard J; de Los Campos, Gustavo; Egan, Scott P et al. (2016) Modelling heterogeneity among fitness functions using random regression. Methods Ecol Evol 7:70-79|
|Danila, M I; Westfall, A O; Raman, K et al. (2015) The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis. Genes Immun 16:446-51|
|Tang, Qi; Danila, Maria I; Cui, Xiangqin et al. (2015) Expression of Interferon-? Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans. Arthritis Rheumatol 67:1165-70|
|Aslibekyan, S; Brown, E E; Reynolds, R J et al. (2014) Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial. Pharmacogenomics J 14:48-53|
|Mikuls, Ted R; Payne, Jeffrey B; Yu, Fang et al. (2014) Periodontitis and Porphyromonas gingivalis in Patients with Rheumatoid Arthritis. Arthritis Rheum :|
|Aslibekyan, Stella; Sha, Jin; Redden, David T et al. (2014) Gene-body mass index interactions are associated with methotrexate toxicity in rheumatoid arthritis. Ann Rheum Dis 73:785-6|
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