Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis
Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis
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DOI：
10.1136/ard.2007.075028
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发表时间：
2008-03-01
影响因子：
27.4
通讯作者：
Merriman, T. R.
中科院分区：
文献类型：
--
作者：
McKinney, C.;Merriman, M. E.;Merriman, T. R.
目的：越来越多的证据表明基因拷贝数变异影响表型变异。趋化因子配体3样蛋白1(CCL3L1)由一个拷贝数可变的基因编码，与多种促炎细胞因子受体结合，包括趋化因子受体5(CCR5)。考虑到β-趋化因子募集淋巴细胞是自身免疫的一个特征，而且CCR5 Delta 32变异与类风湿关节炎(RA)的保护作用有关，我们假设CCL3L1拷贝数影响RA和1型糖尿病(T1D)的易感性。方法：我们检测了来自新西兰(新西兰)和英国的1136例RA、252例新西兰T1D病例和1470例对照的CCL3L1拷贝数。结果：在新西兰队列中，拷贝数大于2(最常见的拷贝数)是RA的危险因素(优势比(OR)1.34，95%CI1.08~1.66，p=0.009)，而不是较小的UK RA队列(OR1.09，95%CI0.75~1.60，p=0.643)。在T1D队列(OR1.46，95%CI0.98-2.20，p=0.064)和合并RA/T1D队列(OR1.30，95%CI1.00-1.54，p=0.003)中有关联的证据。CCL3L1剂量与CCR5基因型之间存在遗传交互作用；CCL3L1拷贝数增加所带来的遗传风险增加可被功能失调的CCR5(CCR5 Delta 32)消除。结论：CCL3L1表达增加可能增强炎症反应，增加自身免疫性疾病的发生几率。遗传相互作用数据与生物学上可信的模型一致；CCR5 Delta 32通过阻断CCR5途径的信号传递来保护RA和T1D，减轻过量CCL3L1的促炎效应。
Objective: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5 Delta 32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D).Methods: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian.Results: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p=0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p=0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p=0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p=0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5 Delta 32).Conclusions: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5 Delta 32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.