title: Association of LY9 in UK and Canadian SLE families.
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.
authors.affiliation: Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK. deborah.cunninghame-graham@imperial.ac.uk
authors.forename: D S
authors.initials: DS
authors.lastname: Cunninghame Graham
authors.forename: T J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: P R
authors.initials: PR
authors.lastname: Fortin
authors.forename: A
authors.initials: A
authors.lastname: Montpetit
authors.forename: Y-c
authors.initials: YC
authors.lastname: Cai
authors.forename: S
authors.initials: S
authors.lastname: Lim
authors.forename: T
authors.initials: T
authors.lastname: McKenzie
authors.forename: L
authors.initials: L
authors.lastname: Farwell
authors.forename: B
authors.initials: B
authors.lastname: Rhodes
authors.forename: L
authors.initials: L
authors.lastname: Chad
authors.forename: T J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: A
authors.initials: A
authors.lastname: Sharpe
authors.forename: C
authors.initials: C
authors.lastname: Terhorst
authors.forename: C M T
authors.initials: CM
authors.lastname: Greenwood
authors.forename: J
authors.initials: J
authors.lastname: Wither
authors.forename: J D
authors.initials: JD
authors.lastname: Rioux
mesh_terms: D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000071176:Signaling Lymphocytic Activation Molecule Family; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015703:Antigens, CD; C430423:LY9 protein, human; D008562:Membrane Glycoproteins; D000071176:Signaling Lymphocytic Activation Molecule Family