A single nucleotide polymorphism in the CCL1 gene predicts acute exacerbations in chronic obstructive pulmonary disease
A single nucleotide polymorphism in the CCL1 gene predicts acute exacerbations in chronic obstructive pulmonary disease
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DOI：
10.1164/rccm.200603-443oc
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发表时间：
2006-10-15
影响因子：
24.7
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Takabatake, Noriaki;Shibata, Yoko;Kubota, Isao
理论基础：慢性阻塞性肺疾病(COPD)急性加重(AEs)是COPD发病率和死亡率的主要原因。目的：宿主防御机制的显著异质性可能归因于炎性趋化因子中的单核苷酸多态性(SNPs)，这些SNPs在经历AEs的COPD患者的呼吸道中表达增强。方法：在276例男性慢性阻塞性肺疾病患者的回顾性和前瞻性研究中，我们研究了CCL11、CCL1和CCL5基因的4个SNPs与AEs的频率和严重程度的关系。测量和主要结果：在2年的回顾性研究中，CCL1基因预测的增强子区域的一个SNIP(国家生物技术信息中心SNP参考：rs2282691)编码一系列白细胞的趋化因子，在显性模型中与AEs的频率显著相关(Fisher精确检验：优势比[OR]，2.70；95%可信区间[CI]，1.36-5.36；P=0.004；Logistic回归：OR3.06；95%可信区间：1.46-6.41；P=0.003；Kruskal-Wallis检验：P=0.003)。在30个月的前瞻性研究中，“A”等位基因是AEs严重程度的显著危险等位基因，具有基因剂量效应(Kaplan-Meier方法和对数等级检验：AA与TT；对数等级统计：7.67，p=0.006；COX比例风险回归方法：OR，5.93；95%CI，1.28-27.48；p=0.023)。C/EBPβ基因是肺部感染的关键转录因子，与T等位基因结合，但不与A等位基因结合。结论：CCL1基因变异可能通过参与机体对AEs的防御机制而与AEs易感性有关。
Rationale: Acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality in COPD.Objectives: The marked heterogeneity in the host defense mechanisms may be attributed to single nucleotide polymorphisms (SNPs) in the inflammatory chemokines that show enhanced expression in the airway of patients with COPD who experience AEs. Methods: We investigated four SNPs of the CCL11, CCL1, and CCL5 genes in relation to the frequency and severity of AEs in retrospective and prospective studies of a cohort of 276 male patients with COPD.Measurements and Main Results: In the 2-yr retrospective study, one SNIP (National Center for Biotechnology Information SNP reference: rs2282691) in the predicted enhancer region of the CCL1 gene, encoding a chemotactic factor for a series of leukocytes, was significantly associated with the frequency of AEs in a dominant model (Fisher's exact test: odds ratio [OR], 2.70; 95% confidence interval [CI], 1.36-5.36; p = 0.004; logistic regression: OR, 3.06; 95% CI, 1.46-6.41; p = 0.003; and Kruskal-Wallis test: p = 0.003). In the 30-mo prospective study, the "A" allele was a significant risk allele for the severity of AEs, with a gene-dosage effect (Kaplan-Meier method with log-rank test: AA vs. TT; log-rank statistic: 7.67, p = 0.006; Cox proportional hazards regression method: OR, 5.93; 95% CI, 1.28-27.48; p = 0.023). The electromobility shift assay showed that C/EBP beta, a key transcriptional factor in response to pulmonary infections, binds to the "T" allele, but not to the "A" allele.Conclusions: Variants in the CCL1 gene are associated with susceptibility to AEs through their potential implication in the host defense mechanisms against AEs.