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

Nature Genetics
Robert R GrahamMarta E Alarcón-Riquelme

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.

References

Jan 1, 1982·Statistics in Medicine·R F Woolson, J A Bean
May 29, 2000·American Journal of Human Genetics·E R MartinN L Kaplan
Feb 27, 2003·Proceedings of the National Academy of Sciences of the United States of America·Emily C BaechlerTimothy W Behrens
Mar 19, 2003·The Journal of Experimental Medicine·Lynda BennettVirginia Pascual
Sep 12, 1957·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·A ISAACS, J LINDENMANN
May 12, 2004·Journal of Urban Health : Bulletin of the New York Academy of Medicine·Maria K MitchellUNKNOWN New York Cancer Project
Jul 23, 2004·Nature·Michael MorleyVivian G Cheung
Aug 17, 2004·The Journal of Biological Chemistry·Betsy J BarnesPaula M Pitha
Dec 14, 2004·Arthritis and Rheumatism·Kyriakos A KirouMary K Crow
Apr 9, 2005·Arthritis and Rheumatism·Donato Alarcón-SegoviaUNKNOWN Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL)
Oct 11, 2005·International Immunology·Kenya HondaTadatsugu Taniguchi
Oct 29, 2005·Nature·UNKNOWN International HapMap Consortium

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Citations

Jan 6, 2010·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Stefan WieczorekJörg T Epplen
Jan 6, 2010·Cancer Immunology, Immunotherapy : CII·David SavitskyTadatsugu Taniguchi
Aug 31, 2006·Springer Seminars in Immunopathology·Maida Wong, Betty P Tsao
Sep 12, 2006·Springer Seminars in Immunopathology·Marta E Alarcón-Riquelme
Oct 6, 2006·Springer Seminars in Immunopathology·John B HarleyKenneth M Kaufman
Sep 20, 2011·Rheumatology International·Wang-Dong Xu, Dong-Qing Ye
Jun 27, 2013·Rheumatology International·Xiuzhi JiaHuan Ren
Sep 12, 2008·Archives of Dermatological Research·Joerg WenzelThomas Tüting
Jan 6, 2012·Human Genetics·José Ezequiel MartínJavier Martín
Jan 5, 2013·Modern Rheumatology·Kiminobu TanizawaTakateru Izumi
Jun 23, 2010·Clinical and Experimental Medicine·Jorge Ramón Padilla-GutiérrezJosé Francisco Muñoz-Valle
Sep 8, 2011·Journal of Clinical Immunology·Masakatsu YanagimachiShumpei Yokota
Feb 9, 2013·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Hui-Feng LiuYa-Ting Tu
Aug 15, 2013·Current Rheumatology Reports·Patrícia Costa-Reis, Kathleen E Sullivan
Aug 7, 2010·Journal of Biosciences·Neeti SharmaSharmila A Bapat
Mar 1, 2008·Journal of Cardiovascular Translational Research·Robert Roberts
Jul 26, 2013·Expert Reviews in Molecular Medicine·Wang-Dong XuDong-Qing Ye
Mar 6, 2008·Nature Clinical Practice. Rheumatology·Ryo Yamada
Dec 7, 2007·Nature Genetics·Deborah S Cunninghame GrahamTimothy J Vyse
Feb 22, 2011·Nature Genetics·Indra AdriantoPatrick M Gaffney
Jan 22, 2008·Nature Genetics·UNKNOWN International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN)Jennifer A Kelly
Feb 29, 2008·Nature Genetics·Sergey NejentsevRolf D Horstmann
Jul 29, 2006·Nature Genetics·Marta E Alarcón-Riquelme
Jan 18, 2011·Nature Immunology·Thomas KrausgruberIrina A Udalova
May 5, 2007·Nature Medicine·Roberto BaccalaArgyrios N Theofilopoulos
Feb 9, 2011·Nature Reviews. Genetics·Ryan TewheyNicholas J Schork
Aug 26, 2006·Nature Reviews. Immunology·Kenya Honda, Tadatsugu Taniguchi
Oct 26, 2006·Nature Reviews. Immunology·Ann Marshak-Rothstein
Jul 26, 2008·Nature Reviews. Immunology·Ramnik J Xavier, John D Rioux
Mar 17, 2012·Nature Reviews. Immunology·David J RawlingsAlmut Meyer-Bahlburg
Jan 5, 2010·Nature Reviews. Rheumatology·John C Hall, Antony Rosen
Nov 10, 2010·Nature Reviews. Rheumatology·Yun Deng, Betty P Tsao
Jul 27, 2011·Nature Reviews. Rheumatology·Regina K Cheung, Paul J Utz
Oct 7, 2008·Nature Structural & Molecular Biology·Weijun ChenWilliam E Royer
Jun 15, 2007·Genes and Immunity·I Ferreiro-NeiraA Gonzalez
Jun 22, 2007·Genes and Immunity·C Kyogoku, N Tsuchiya
Mar 23, 2007·The New England Journal of Medicine·Peter K Gregersen
Jan 22, 2008·The New England Journal of Medicine·Geoffrey HomTimothy W Behrens
May 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·David A SavitskyKenya Honda

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