Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study
Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study
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DOI：
10.1093/hmg/ddl395
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发表时间：
2006-11-01
影响因子：
3.5
通讯作者：
Vyse, Timothy J.
中科院分区：
文献类型：
--
作者：
Graham, D. S. Cunninghame;Wong, A. K.;Vyse, Timothy J.
CD28、CTLA4（细胞毒性T淋巴细胞相关蛋白4）和ICOS（诱导型T细胞共刺激因子）是系统性红斑狼疮（SLE）的良好候选基因，因为它们在调节T细胞活化方面发挥作用。CTLA4抑制cd28介导的T细胞活化。CTLA4在CD4+和CD8+活化的T细胞上表达，也在B细胞上表达，但CD28和ICOS主要局限于T细胞。在两次全基因组连锁扫描中，2q33染色体上包含CD28-CTLA4-ICOS位点的区间与狼疮有关。这项在532个英国SLE家族中进行的大型家族关联研究首次在该位点进行了80个snp的高密度遗传筛选。整个基因座有7个单倍型块。在CTLA4中，最强的信号来自两个变体，位于3'-UTR下游2.1 kb处。这些多态性rs231726 （SNP 43）和rs231726 （SNP 44）处于完全连锁不平衡（LD） （r(2)=1），与SLE相关P=0.0008 （GH）和P=0.01（基于家族的关联检验）。CTLA4/ICOS启动子远端3′侧区也有信号（P=0.003）。CTLA4的启动子或编码区与SLE的关联尚未得到证实。这些SLE风险等位基因比在Graves病中发现的更远，并且在LD中，在CTLA4的这两个区域都发现了Graves病保护等位基因（Ueda et al. 2003）。这些因素表明了一种特殊的关联模式。相关多态性的功能后果可能影响CTLA4的表达，尽管遗传调节的ICOS表达可能与SLE易感性有关。
CD28, CTLA4 (cytotoxic T lymphocyte-associated protein 4) and ICOS (inducible T cell co-stimulator) are good candidate genes for systemic lupus erythematosus (SLE) because of their role in regulating T cell activation. CTLA4 inhibits CD28-mediated T cell activation. CTLA4 is expressed on CD4+ and CD8+ activated T cells, and also B cells, but CD28 and ICOS are largely restricted to T cells. An interval encompassing the CD28-CTLA4-ICOS locus on chromosome 2q33 was linked to lupus in two genome-wide linkage scans. This large family-based association study in 532 UK SLE families represents the first high-density genetic screen of 80 SNPs at this locus. There are seven haplotype blocks across the locus. In CTLA4, the strongest signal comes from two variants, located 2.1 kb downstream from the 3'-UTR. These polymorphisms, rs231726 (SNP 43) and rs231726 (SNP 44), are in complete linkage disequilibrium (LD) (r(2)=1) and are associated with SLE P=0.0008 (GH) and P=0.01 (family-based association test). There is also a signal in the distal 3' flanking region of CTLA4/ICOS promoter (P=0.003). There was no confirmation of published associations for SLE in the promoter or coding region of CTLA4. These SLE risk alleles are more distal than those identified in Graves' disease and are in LD with Graves' disease protective alleles identified in both of these regions of CTLA4 (Ueda et al. 2003). These factors suggest an SLE-specific pattern of association. The functional consequences of the associated polymorphisms are likely to influence CTLA4 expression, although it is possible that genetically modulated ICOS expression is involved in SLE susceptibility.