Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology Volume 2012, Article ID 594056, 12 pages doi:10.1155/2012/594056 Research Article Effects of IRF5 Lupus Risk Haplotype on Pathways Predicted to Influence B Cell Functions Joel M. Guthridge, 1 Daniel N. Clark, 2 Amanda Templeton, 1 Nicolas Dominguez, 1 Rufei Lu, 1 Gabriel S. Vidal, 1 Jennifer A. Kelly, 1 Kenneth M. Kauffman, 3 John B. Harley, 3 Patrick M. Gaffney, 1 Judith A. James, 1, 4 and Brian D. Poole 1, 2 1 Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA 2 Department of Microbiology and Molecular Biology, Brigham Young University, 857 WIDB, Provo, UT 84604, USA 3 Division of Rheumatology, Cincinnati Children’s Hospital, 3333 Burnet Avenue, Cincinnati, OH 45229, USA 4 Departments of Medicine and Pathology, The University of Oklahoma Health Sciences Center, 1100 N. Lindsay, Oklahoma City, OK 73104, USA Correspondence should be addressed to Brian D. Poole, bpoole@gmail.com Received 5 May 2011; Revised 4 November 2011; Accepted 5 November 2011 Academic Editor: Timothy B. Niewold Copyright © 2012 Joel M. Guthridge et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (P = 0.011), while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE. 1. Introduction Systemic lupus erythematosus is a complex disease with multifactorial etiology and pathogenesis. Studies in identical twins indicate that concordance for lupus is approximately 40%, indicating a strong but not exclusive genetic compo- nent [1, 2]. Recent genetic analyses have identified more than thirty candidate genes that are associated with lupus risk [3– 18]. IRF5 was found to be associated with lupus by multiple independent groups in a variety of populations [10, 13–15, 19, 20]. IRF5 risk haplotypes may function at the crossroads of environmental risk, such as virus infection, and cellular immune responses. At least three polymorphisms of IRF5 have been identified that contribute independently to the risk for lupus, which together constitute the lupus risk haplotype [10, 21]. Although the majority of the polymorphisms that have been associated with lupus are in nontranslated regions, they may affect several facets of IRF5 activity, including splicing, RNA stability, transcription factor binding, and apoptosis [9, 10, 15, 21, 22]. IRF5 is important in the production of and response to interferon alpha (IFNα), which is heightened in lupus. IFNα is produced by dendritic cells, macrophages, B cells, and other cell types, primarily in response to virus infection [23, 24]. Dendritic cells have been shown to produce IFNα in response to incubation with immune complex-containing