1. ¹Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK
2. ²University 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
3. ³McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada
4. ⁴Toronto Western Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
5. ⁵Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
6. ⁶The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA, USA
7. ⁷Harvard Medical School, Pathology, NRB-837, Boston, MA, USA
8. ⁸Division of Immunology, BIDMC, Harvard Institute of Medicine, Boston, MA, USA
9. ⁹Arthritis 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
10. ¹⁰University of Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec, Canada

Correspondence: Dr DS Cunninghame Graham, Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, Hammersmith Campus, First Floor J Block, Room 118/119, Du Cane Road, London W12 ONN, UK. E-mail: deborah.cunninghame-graham@imperial.ac.uk

¹¹This is a co-second author.

¹²This is a co-last author.

¹³The complete list is shown in the Appendix.

Received 17 September 2007; Revised 23 November 2007; Accepted 26 November 2007; Published online 24 January 2008.

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.