Association of LY9 in UK and Canadian SLE families
Association of LY9 in UK and Canadian SLE families
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DOI：
10.1038/sj.gene.6364453
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发表时间：
2008-03-01
影响因子：
5
通讯作者：
Rioux, J. D.
中科院分区：
文献类型：
--
作者：
Graham, D. S. Cunninghame;Vyse, T. J.;Rioux, J. D.
系统性红斑狼疮（SLE）是一种病因不明的复杂疾病。人类SLE的全基因组连锁研究确定了几个连锁区域，包括1 q23，其中包含多个易感基因，包括信号淋巴细胞活化分子（SLAM）基因座的成员。在小鼠中有一个同线连接区，Sle 1。SLAM基因是功能相关的细胞表面受体，其调节免疫系统中细胞的信号转导。在英国和加拿大SLE家族中进行的基于家族的关联研究确定了SLAMF 7和LY 9启动子和编码区的变异与SLE疾病易感性有关。最强的关联来自LY 9外显子8的rs 509749（P = 0.00209）。rs 509749编码LY 9胞质结构域中氨基酸602的瓦尔/Met非同义变化。在来自加拿大SLE家族的父母和受影响的个体中，rs 509049的风险等位基因通过增加CD 8+记忆T细胞的数量，同时降低CD 4+幼稚T细胞和活化T细胞的比例来扭曲T细胞群体。由于rs 509749位于SAP/SH 2D 1a的共有结合位点内，其影响来自LY 9的下游信号传导事件，因此增加的CD 8+记忆T细胞的机制可能包括SAP/SH 2D 1a与LY 9的胞质结构域的差异结合。
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+ naive 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.