A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus

Robert R Graham^1, 9, Sergey V Kozyrev^2, 9, Emily C Baechler^3, 9, M V Prasad Linga Reddy^2, 9, Robert M Plenge¹, Jason W Bauer³, Ward A Ortmann³, Thearith Koeuth³, Ma Francisca González Escribano⁴, the Argentine and Spanish Collaborative Groups, Bernardo Pons-Estel⁵, Michelle Petri⁶, Mark Daly¹, Peter K Gregersen⁷, Javier Martín⁸, David Altshuler¹, Timothy W Behrens³ & Marta E Alarcón-Riquelme²

¹  Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA, and the Center for Human Genetics Research and Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

²  Department of Genetics and Pathology, Unit of Medical Genetics, Rudbcek Laboratory, Uppsala University, Uppsala 75185, Sweden.

³  Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.

⁴  Servicio de Inmunología, Hospital Virgen del Rocio, Sevilla 41013, Spain.

⁵  Sanatorio Parque, Rosario 2000, Argentina.

⁶  Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

⁷  The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA.

⁸  Instituto de Biomedicina López-Neyra, Consejo Superior de Investigación Científica (CSIC), Granada 18100, Spain.

⁹  These authors contributed equally to this work.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease¹ characterized by activation of the type I interferon (IFN) pathway^{2, 3, 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.

	Top