Abstract
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.
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Acknowledgements
This study was funded by the Canadian Institutes of Health Research CIHR NSP 94825, CIHR 62843, Toronto Western Research Institute, Department of Medicine, University of Toronto. CaNIOS is partly supported by funds from the Arthritis and Autoimmunity Research Centre Foundation at University Health Network, and matching funds provided by Lupus Canada and its member provincial organizations.We thank all the subjects in this study: the SLE patients and their parents. We would also like to thank Catherine Labbé and Mariana Chagas for helpful discussions and critical reading of the paper.
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GenES study
Paul R Fortin, Joan Wither, John Rioux, Glinda Cooper and Celia MT Greenwood are the principal investigators of the Genetic and Environmental Factors in SLE Study.
CaNIOS GenES investigators
Janet Pope: Division of Rheumatology, St Joseph's Health Centre, London, Ontario, Canada. Dafna Gladman, Murray Urowitz: University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network and Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
John Hanly: Division of Rheumatology, Department of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
C Douglas Smith: Division of Rheumatology, Ottawa Hospital, Ottawa, Ontario, Canada.
Ann Clarke, Sasha Bernatsky, Christian Pineau: Division of Rheumatology, McGill University Health Center, Montreal, Quebec, Canada.
Thomas Hudson: Ontario Institute for Cancer Research, and Department of Medical Genetics and Microbiology, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Christine Peschken, Carol Hitchon: Winnipeg Health Science Center, Winnipeg, Manitoba, Canada.
Michel Zummer: Department of Rheumatology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Susan Barr: Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Gilles Boire: Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Eric Rich, Jean-Luc Senécal: Division of Rheumatology, Centre Hospitalier de l’Université de Montréal, Department of Medicine, University of Montreal School of Medicine, Montreal, Quebec, Canada.
Simon Carette, Robert Inman: Toronto Western Hospital, University Health Network and Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
We are indebted to the following CaNIOS research assistants/coordinators for their work in the GenES project
Jiandong Su is CaNIOS Database Administrator.
Tamara McKenzie: GenES Study National Coordinator, Division of Rheumatology, Toronto Western Hospital, University Health Network.
Sara Hewitt, Janine Ouimet: Division of Rheumatology, St Joseph's Health Centre, London, Ontario, Canada.
Diona Dobaille, Menisha Hodge, Tammy Koonthanan, Kiran Pabla, Yang Zhou: Division of Rheumatology, Toronto Western Hospital, University Health Network.
Tina Linehan: Division of Rheumatology, Department of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
Kathryn Drouin: Division of Rheumatology, Ottawa Hospital, Ottawa, Ontario, Canada.
Nancy Branco, Elizabeth Piniero: Division of Clinical Epidemiology, Montreal General Hospital and McGill University, Montreal, Quebec, Canada.
Andrea Craig, Diane Ferland, Donna Hart: Winnipeg Health Science Center, Winnipeg, Manitoba, Canada.
Diane Ferland: Department of Rheumatology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Whitney Steber, Patrice Nedinis: Calgary Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada.
Celine Boulet, Isabelle Gagnon: Department of Medicine, Division of Rheumatology, University of Sherbrooke, Sherbrooke, Quebec, Canada.
Diane Therrien: Division of Rheumatology, Hôpital Notre-Dame, Montreal, Quebec, Canada.
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Budarf, M., Goyette, P., Boucher, G. et al. A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles. Genes Immun 12, 51–58 (2011). https://doi.org/10.1038/gene.2010.47
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DOI: https://doi.org/10.1038/gene.2010.47
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