Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Its cause is unknown, but both genetic and environmental factors are involved. Emerging data show that genetic variants associated with RA differ by race/ethnicity. RA is uncommon in black Africans, but it is common among African-Americans, suggesting that there may be protective factors in ancestral Africans. Osteoporosis, a common co-morbid condition with RA, is much less common among African-Americans than among persons of European ancestry. Genetic factors associated with RA and its radiographic severity have been extensively studied in persons of European and of Asian ancestry, but the lack of large datasets has precluded similar analyses in African-Americans. We are uniquely positioned to analyze the genetics of RA in African- Americans through the extensive data collected from the NIH-funded CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) Registry, its funded ancillary studies, and other data collections. We seek to identify genetic influences on susceptibility to, or protection from, RA in African-Americans by analyzing a total of 3,200 African-Americans.
In Aim 1, we will perform a genome-wide association study (GWAS) using the Illumina Human 1M Duo BeadChip in 1,600 African-Americans (800 with anti-CCP+ RA and 800 controls).
Aim 2 will replicate and extend these findings by analyzing ~12,000 single nucleotide polymorphisms (SNPs) in an independent set of 1,600 African-Americans (800 CCP+ RA patients and 800 controls).
In Aim 3, we will perform additional mapping of the genetic regions associated with RA. In addition, we will perform exploratory analyses of genetic data with existing data on RA-related phenotypes, including radiographic severity at 3 years disease duration, and bone mineral density in early RA and controls. We will also use existing gene expression microarray data from peripheral blood mononuclear cells in CLEAR patients to identify expression quantitative trait loci (eQTL) (nearby or distant genetic variants that influence gene expression), particularly those associated with radiographic severity of RA. This proposal will translate advances in clinical rheumatology, biotechnology, and statistical genetics into new information to improve diagnosis, or assessment of prognosis, or develop targeted therapies for RA in African-Americans.

Public Health Relevance

Project Narrative Rheumatoid arthritis (RA), a common autoimmune arthritis, involves both genetic and environmental factors. We are uniquely positioned to perform the first large-scale genetic analyses of African-American RA patients and healthy controls through the NIH-sponsored CLEAR Registry (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) and other data collections. We will also use these genetic data to gain new insights into RA-related conditions in African-Americans, such as radiographic damage of joints, osteoporosis, and factors that turn on or off expression of genes in blood cells.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-H (02))
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Wang, Yan Z
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Govind, Nimmisha; Choudhury, Ananyo; Hodkinson, Bridget et al. (2014) Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans. Mol Med 20:341-9
Danila, Maria I; Reynolds, Richard J; Tiwari, Hemant K et al. (2013) Ethnic-specific genetic analyses in rheumatoid arthritis: incremental gains but valuable contributions to the big picture. Arthritis Rheum 65:3014-6
Mikuls, Ted R; Levan, Tricia; Gould, Karen A et al. (2012) Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans. Arthritis Rheum 64:655-64
Perkins, Elizabeth A; Landis, Dawn; Causey, Zenoria L et al. (2012) Association of single-nucleotide polymorphisms in CCR6, TAGAP, and TNFAIP3 with rheumatoid arthritis in African Americans. Arthritis Rheum 64:1355-8
Kurreeman, Fina A S; Stahl, Eli A; Okada, Yukinori et al. (2012) Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12. Am J Hum Genet 90:524-32
Hughes, Laura B; Reynolds, Richard J; Brown, Elizabeth E et al. (2010) Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in persons of European ancestry confer risk of rheumatoid arthritis in African Americans. Arthritis Rheum 62:3547-53