Genetic Polymorphisms in Tumor Necrosis Factor (TNF)- and TNF- in a Population-Based Study of Systemic Lupus Erythematosus: Associations and Interaction with the Interleukin-1-889 C/T Polymorphism Christine G. Parks, Janardan P. Pandey, Mary Anne Dooley, Edward L. Treadwell, E.W. St. Clair, Gary S. Gilkeson, Carol A. Feghali-Bostwick, and Glinda S. Cooper ABSTRACT: Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF--308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymor- phisms in TNF- (-308G/A, -238G/A) and TNF (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE as- sociations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1-889C/T polymorphism, previously linked to SLE in this population. Genotypes were ana- lyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver’s license registries. Carriage of the TNF- -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1-889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF--308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 geno- types in Caucasians, and yielded a strong association (OR = 8.0, p  0.00001) for the combined “HLA-DR3, TNF--308A, IL-1-889C/C” genotype. These find- ings provide evidence of cytokine gene epistasis in SLE susceptibility. Human Immunology 65, 622– 631 (2004). © American Society for Histocompatibility and Immu- nogenetics, 2004. Published by Elsevier Inc. KEYWORDS: TNF; polymorphism; systemic lupus er- ythematosus; population-based; genetics ABBREVIATIONS CI confidence interval IL interleukin OR odds ratio SLE systemic lupus erythematosus TNF tumor necrosis factor INTRODUCTION Tumor necrosis factor (TNF) is well known for its role in the regulation of inflammation and apoptosis, two pro- cesses involved in the pathogenesis of systemic lupus erythematosus (SLE). Production of TNF is altered in SLE patients and correlated with disease activity [1–3]. Experimental models of SLE show abnormal TNF activ- ity [4–6], which can be manipulated to change patterns of disease onset or severity [7, 8]. In some models, From the National Institute of Environmental Health Sciences, Durham, NC (C.G.P., G.S.C.); Medical University of South Carolina, Charleston, SC (J.P.P., G.S.G.), University of North Carolina Medical School, Chapel Hill, NC (M.A.D.); East Carolina University School of Medicine, Green- ville, NC (E.L.T.); Duke University Medical Center, Durham, NC (E.W.S.C.); University of Pittsburgh, Pittsburgh, PA (C.L.F-B.). Address reprint requests to: Christine G. Parks, PhD, Epidemiology Branch, A3-05, NIEHS, PO Box 12233, Durham, NC 27709-12233; Tel: (919) 541-2577; Fax: (919) 541-2511; E-mail: parks@niehs.nih.gov. Funded in part by an NIH Intramural Research Training Award and the U.S. Department of Energy cooperative agreement DE-FC09- 02CH11109. The Carolina Lupus Study was supported by the Intramural Research Program of the NIEHS and the National Center for Minority Health and Health Disparities of the NIH. Received December 1, 2003; revised March 9, 2004; accepted March 11, 2004. Human Immunology 65, 622– 631 (2004) © American Society for Histocompatibility and Immunogenetics, 2004 0198-8859/04/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2004.03.001