Rheumatoid arthritis (RA) is a systemic inflammatory disease that leads to progressive joint destruction, disability, and accelerated mortality. Factors that influence autoantibody production and disease everity in RA have not been fully defined. However, there is increasing data showing that cigarette smoking, associated with disease susceptibility, is also associated with RA outcome and its effect is likely modified by multiple genetic factors including HLA-DRB1 alleles encoding the shared epitope (SE) and drug metabolizing enzyme (DME) polymorphisms. Studies examining RA severity have focused on the interaction of smoking with single gene polymorphisms in groups that have almost exclusively included Caucasian women. This is an important distinction because smoking, in terms of RA risk (particularly for autoantibody positive disease), has its greatest impact in men while other smoking related illnesses disproportionately impact non-Caucasians. We will examine determinants of autoantibody production and disease severity in 800 subjects (including 600 Caucasian men) from the Veterans Affairs RA (VARA) cohort and 400 African Americans from the NIH-funded Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) registry. The overall hypothesis of this study is that smoking is associated with greater autoantibody production and more severe RA and the effect of this environmental exposure is modified by multiple gene-smoking interactions.
The aims of this study are to examine: 1) associations of smoking with autoantibody levels and radiographic measures, 2) associations of DME polymorphisms with these outcomes, and 3) the role of gene-smoking interactions relevant to these outcomes. In addition to SE, genetic factors to be studied will include DME polymorphisms (in genes encoding N-acetyltransferase [NAT]1, NAT2, microsomal epoxide hydrolase, and glutathione S-transferase), and protein tyrosine phosphatase (PTPN22). RA-specific outcomes that will be examined include radiographic measures (modified Sharp score), nodules, rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) antibody. In addition to traditional statistical approaches, a novel recursive partitioning technique will be used that will allow for the detection simultaneous interactions among multiple candidate genes and smoking. We anticipate that the results of this study will be extended to other RA populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR054539-03
Application #
7618669
Study Section
Special Emphasis Panel (ZAR1-EHB-M (O1))
Program Officer
Wang, Yan Z
Project Start
2007-05-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2009
Total Cost
$73,500
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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
Kerr, Gail S; Sabahi, Iraj; Richards, John S et al. (2011) Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 38:53-9
Mikuls, Ted R; Fay, Brian T; Michaud, Kaleb et al. (2011) Associations of disease activity and treatments with mortality in men with rheumatoid arthritis: results from the VARA registry. Rheumatology (Oxford) 50:101-9
Craig, Steven M; Yu, Fang; Curtis, Jeffrey R et al. (2010) Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol 37:275-81
Mikuls, Ted R; Gould, Karen A; Bynote, Kimberly K et al. (2010) Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione S-transferase in a cross-sectional study. Arthritis Res Ther 12:R213
Mikuls, Ted R; Sayles, Harlan; Yu, Fang et al. (2010) Associations of cigarette smoking with rheumatoid arthritis in African Americans. Arthritis Rheum 62:3560-8
Miriovsky, Benjamin J; Michaud, Kaleb; Thiele, Geoffrey M et al. (2010) Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis. Ann Rheum Dis 69:1292-7
Mikuls, Ted R; Payne, Jeffrey B; Reinhardt, Richard A et al. (2009) Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int Immunopharmacol 9:38-42
Curtis, J R; Arora, T; Donaldson, M et al. (2009) Skeletal health among African Americans with recent-onset rheumatoid arthritis. Arthritis Rheum 61:1379-86
Mikuls, T R; Hughes, L B; Westfall, A O et al. (2008) Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis. Ann Rheum Dis 67:1529-34

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