Interactions of Cigarette Smoking with NAT2 Polymorphisms Impact Rheumatoid Arthritis Risk in African Americans

• Type of Material: Article
• Authors: Ted R. Mikuls, University of Nebraska Medical Center; Tricia LeVan, University of Nebraska Medical Center; Karen A. Gould, University of Nebraska Medical Center; Fang Yu, University of Nebraska Medical Center; Geoffrey M. Thiele, University of Nebraska Medical Center; Kimberly K. Bynote, University of Nebraska Medical Center; Doyt Conn, Emory University; Beth L. Jonas, University of North Carolina; Leigh F. Callahan, University of North Carolina; Edwin Smith, Emory University; Richard Brasington, Washington University; Larry W. Moreland, University of Pittsburgh; Richard Reynolds, University of Alabama; Angelo Gaffo, University of Alabama; S. Louis Bridges, University of Alabama
• Language: English
• Date: 2012-03-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2012 by the American College of Rheumatology.
• Final Published Version (URL): http://dx.doi.org/10.1002/art.33408
• Title of Journal or Parent Work: Arthritis and Rheumatism
• ISSN: 0004-3591
• Volume: 64
• Issue: 3
• Start Page: 655
• End Page: 664
• Grant/Funding Information: The CARDIA study is supported by the NIH (grants N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, and N01-HC-95095).; Supported by the South Carolina Clinical and TranslationalResearch Institute (NIH Center for Research Resources grant UL1-RR-029882) and the University of Alabama at Birmingham Center for Clinical and Translational Studies (NIH Center for Research Re-sources grant 5UL1-RR-025777-03).; Dr. Mikuls’ work was supported by the Nebraska Arthritis Outcomes Research Center, the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R03-AR-054539 and K23-AR-050004), the Arthritis Foundation (national organization and the Nebraska chapter), and the Veterans Affairs Office of Research and Development (VA Merit award).; The CLEAR Registry is supported by the NIH (grant N01-AR-02247, and grant N01-AR-6-2278 to Dr. Bridges, Principal Investigator).
• Keywords: SLOW ACETYLATION; SUSCEPTIBILITY; ENVIRONMENT INTERACTION; METABOLIZING ENZYMES; Science & Technology; SHARED EPITOPE; GLUTATHIONE-S-TRANSFERASE; Rheumatology; GENOTYPE; ASSOCIATION; Life Sciences & Biomedicine; COLORECTAL-CANCER; LUNG-CANCER RISK
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Objective To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. Methods Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed. Results There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P additive = 0.000003) and rs1208 (P additive = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies. Conclusion Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.