Systemic lupus erythematosus (SLE) is a complex autoimmune disease1 characterized by activation of the type I interferon (IFN) pathway2-4. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE5 in four independent case-control cohorts (P = 4.4 × 10-16) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5′ donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.
Bibliographical noteFunding Information:
We thank H. Yin and the members of the Uppsala Genome Center for help with sequencing and S. Young, J. Novitzke, L. Kyle, K. Espe, C. Gillett, P. Gaffney and K. Moser for assistance. The Swedish samples were obtained from the Lupus cohort at Karolinska University Hospital, Solna. This work was supported by grants from the Swedish Research Council (M.E.A.-R.), the Clas Groschinski Foundation (M.E.A.-R.), the Marcus Borsgtröms Foundation (M.E.A.-R.), the Torsten and Ragnar Söderberg’s Foundation (M.E.A.-R.), the Swedish Association against Rheumatism (M.E.A.-R.), the Alliance for Lupus Research (M.E.A.-R., T.W.B.), the Lupus Research Institute (T.W.B.), the Mary Kirkland Center for Lupus Research (T.W.B.), the Lupus Foundation of Minnesota (T.W.B.), the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIH) (T.W.B.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH (R.R.G., E.C.B., T.W.B.) and the Ministerio de Ciencia y Tecnología (SAF2003-3460; J.M.). The Johns Hopkins Lupus Cohort is supported by NIH grant AR 43727, and the Johns Hopkins General Clinical Research Center is supported by NIH M01-RR-00052.