title: A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozyrev
authors.forename: Emily C
authors.initials: EC
authors.lastname: Baechler
authors.forename: M V Prasad Linga
authors.initials: MV
authors.lastname: Reddy
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Jason W
authors.initials: JW
authors.lastname: Bauer
authors.forename: Ward A
authors.initials: WA
authors.lastname: Ortmann
authors.forename: Thearith
authors.initials: T
authors.lastname: Koeuth
authors.forename: Ma Francisca
authors.initials: MF
authors.lastname: González Escribano
authors.forename: Bernardo
authors.initials: B
authors.lastname: Pons-Estel
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012326:RNA Splicing / Q000502:physiology*
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors