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Association of LY9 in UK and Canadian SLE families

Genes & Immunity volume 9, pages 93–102 (2008)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is a complex disease trait of unknown aetiology. Genome-wide linkage studies in human SLE identified several linkage regions, including one at 1q23, which contains multiple susceptibility genes, including the members of the signalling lymphocyte activation molecule (SLAM) locus. In mice there is a syntenic linkage region, Sle1. The SLAM genes are functionally related cell-surface receptors, which regulate signal transduction of cells in the immune system. Family-based association study in UK and Canadian SLE families identified variants in the promoter and coding region of SLAMF7 and LY9 contributing to SLE disease susceptibility. The strongest association was from rs509749, in exon 8 of LY9 (P=0.00209). rs509749 encodes a Val/Met nonsynonymous change in amino acid 602 in the cytoplasmic domain of LY9. In the parents and affected individuals from the Canadian SLE families, the risk allele of rs509049 skews the T-cell population by increasing the number of CD8+ memory T cells, while decreasing the proportion of CD4+ naïve T cells and activated T cells. Since rs509749 lies within the consensus binding site for SAP/SH2D1a, which influences downstream signalling events from LY9, the mechanism for increased CD8+ memory T cells may include differential binding SAP/SH2D1a to the cytoplasmic domain of LY9.

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Acknowledgements

This work was funded by a grant from the National Institutes of Allergy and Infectious Diseases (AI065687) to Timothy J Vyse, John D Rioux and Cox Terhorst and Arlene Sharpe, through a Senior Fellowship Award from the Wellcome Trust to Timothy J Vyse and by a grant from the Canadian Institutes of Health Research (no. 62840) to Joan Wither and Paul Fortin. We acknowledge the work of Christine Stevens and Angela Richardson for help with the genotyping of the UK samples, Andrew Wong and Paul Spencer in recruiting patients and families into the study and we would like to thank our clinical colleagues for helping us recruit study participants. Our thanks and appreciation is extended to all the patients and their relatives for generously donating blood samples and all the general practitioners and practice nurses for collecting them. We appreciate the contribution to the genotyping from the Broad Institute Center for Genotyping and Analysis, which is supported by grant U54 RR020278-01 from the National Center for Research Resources. We appreciate the contribution to CaNIOS studies made by the Arthritis and Autoimmune Research Centre Foundation and by Lupus Canada. Dr Fortin's salary is supported in part by a Distinguished Senior Research Investigator Award from The Arthritis Society (Canada) and the Arthritis Centre of Excellence, University of Toronto. We thank Glinda Cooper, a GenES co-investigator, for helpful discussions and Jaime O Claudio, the National Scientific and Development Coordinator for CaNIOS for assistance in preparation of the article and Jiandong Su, CaNIOS Database Administrator for assistance with management of the GenES database. We also acknowledge the investigators who contributed patients to the study (see Appendix).

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Author notes

  1. D S Cunninghame Graham, T J Vyse, P R Fortin, A Montpetit, Y-c Cai, S Lim, T McKenzie, L Farwell, B Rhodes, L Chad, T J Hudson, A Sharpe, C Terhorst, C M T Greenwood, J Wither and J D Rioux: T J Vyse and P R Fortin: This is a co-second author.

  2. J Wither and J D Rioux: This is a co-last author.

  3. The complete list is shown in the Appendix.

Authors and Affiliations

  1. Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK

    D S Cunninghame Graham, T J Vyse & B Rhodes

  2. University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network; Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    P R Fortin

  3. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada

    A Montpetit, L Chad & T J Hudson

  4. A Montpetit, L Chad & T J Hudson

  5. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    P R Fortin

  6. Toronto Western Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Y-c Cai & T McKenzie

  7. Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

    S Lim & C M T Greenwood

  8. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA, USA

    L Farwell

  9. Harvard Medical School, Pathology, NRB-837, Boston, MA, USA

    A Sharpe

  10. Division of Immunology, BIDMC, Harvard Institute of Medicine, Boston, MA, USA

    C Terhorst

  11. Arthritis Centre of Excellence; Division of Genetics and Development, Toronto Western Hospital Research Institute, University Health Network; Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada

    J Wither

  12. University of Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec, Canada

    J D Rioux

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Correspondence to D S Cunninghame Graham.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Appendix

Appendix

CaNIOS GenES Investigators are as follows. Janet Pope: Division of Rheumatology, St Joseph's Health Centre, London, Ontario, Canada; Dafna Gladman and Murray Urowitz: University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network; 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 and Christian Pineau: Division of Rheumatology, McGill University Health Center, Montreal, Quebec, Canada; Christine Peschken and 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 Senecal: Division of Rheumatology, Centre Hospitalier de l'Université de Montréal, Department of Medicine, University of Montreal School of Medicine, Montreal, Quebec, Canada; Simon Carette and Robert Inman: Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; and the CaNIOS research assistants/coordinators that recruited the patients: Sara Hewitt and Janine Ouimet: Division of Rheumatology, St Joseph's Health Centre, London, Ontario, Canada; Tamara McKenzie, Diona Dobaille, Menisha Hodge, Tammy Koonthanan, Kiran Pabla and 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 and Elizabeth Piniero: Division of Clinical Epidemiology, Montreal General Hospital, and McGill University, Montreal, Quebec, Canada; Andrea Craig, Diane Ferland, and Donna Hart: Winnipeg Health Science Center, Winnipeg, Manitoba, Canada Winnipeg; Diane Ferland: Department of Rheumatology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada; Whitney Steber and Patrice Nedinis: Calgary Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada; Celine Boulet and Isabelle Gagnon: Department of Medicine, Division of Rheumatology, University of Sherbrooke, Sherbrooke, Quebec, Canada and Diane Therrien: Division of Rheumatology, Hôpital Notre-Dame, Montreal, Quebec, Canada.

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Graham, D., Vyse, T., Fortin, P. et al. Association of LY9 in UK and Canadian SLE families. Genes Immun 9, 93–102 (2008). https://doi.org/10.1038/sj.gene.6364453

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