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Nat Genet DOI:10.1038/ng1782

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

Publication TypeJournal Article
Year of Publication2006
AuthorsGraham, RR, Kozyrev, SV, Baechler, EC, Reddy, MVPrasad L, Plenge, RM, Bauer, JW, Ortmann, WA, Koeuth, T, Escribano, MFrancisca, Pons-Estel, B, Petri, M, Daly, M, Gregersen, PK, Martín, J, Altshuler, D, Behrens, TW, Alarcón-Riquelme, ME
Corporate AuthorsArgentine and Spanish Collaborative Groups
JournalNat Genet
Date Published2006 May
KeywordsCase-Control Studies, Cohort Studies, Genotype, Haplotypes, Humans, Interferon Regulatory Factors, Lupus Erythematosus, Systemic, Molecular Sequence Data, Polymorphism, Genetic, RNA Splicing

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.


Alternate JournalNat. Genet.
PubMed ID16642019
Grant ListAR 43727 / AR / NIAMS NIH HHS / United States
M01-RR-00052 / RR / NCRR NIH HHS / United States