A novel polymorphism in CDC6 is associated with the decline in lung function of ex-smokers in COPD
A novel polymorphism in CDC6 is associated with the decline in lung function of ex-smokers in COPD
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DOI：
10.1016/j.bbrc.2009.02.080
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发表时间：
2009-04-17
影响因子：
3.1
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Takabatake, Noriaki;Toriyama, Sayumi;Kubota, Isao
戒烟对晚期慢性阻塞性肺疾病（COPD）患者肺功能下降率的影响尚未明确。酿酒酵母细胞分裂周期6同源蛋白（CDC 6）具有促凋亡特性。我们验证了我们的假设，即晚期COPD患者戒烟后肺功能快速下降的个体易感性归因于CDC 6基因的遗传变异。我们在30个月内前瞻性地随访了82例患者（戒烟者），并评估了CDC 6基因内和周围10个单核苷酸多态性（SNP）基因型之间FEV（1.0）年下降率（%预测值）的差异。我们发现SNP 5（国家生物技术信息中心SNP参考：rs 2077464）存在显著差异。SNP 6（rs 13706）、SNP 7（rs7217852）和SNP 8（rs 9904270）具有基因剂量效应（ANOVA总体-P = 0.029-0.030）。SNP 5G、SNP 6A、SNP 7 G和SNP 8 T的单个等位基因与FEV1.0（%预测值）的快速下降相关[比值比（95%置信区间）= 2.35（1.194.65），P = 0.0141]。SNP 5G/SNP 6A/SNP 7 G/SNP 8 T单倍型与FEV（1.0）（%预测值）恶化风险增加相关（P = 0.017）。重要的是，SNP 6引起了CDC 6蛋白（Val 441 Ile）中氨基酸的变化，该变化紧邻凋亡期间CDC 6（Asp 442）的caspase-3依赖性切割位点的上游。这些结果表明，CDC 6可能是导致这些COPD患者在戒烟后肺功能快速下降的易感基因之一。(C)2009 Elsevier Inc. All rights reserved.
The effect of smoking cessation on the rate of decline in lung function in patients with advanced stages of chronic obstructive pulmonary disease (COPD) has not been clarified. Saccharomyces cerevisiae cell division cycle 6 homolog (CDC6) protein possesses the pro-apoptotic properties. We tested our hypothesis that the individual susceptibility to rapid decline in lung function despite smoking cessation in patients with advanced stages of COPD is attributed to the genetic variants in the CDC6 gene. We prospectively followed 82 patients (ex-smokers) during 30 months and evaluated the differences among the genotypes in the annual rate of decline in FEV(1.0) (%predicted) with ten single nucleotide polymorphisms (SNPs) in and around the CDC6 gene. We found significant differences in SNP5 (National Center for Biotechnology Information SNP reference: rs2077464). SNP6 (rs13706), SNP7 (rs7217852), and SNP8 (rs9904270) with a gene-dosage effect (ANOVA overall-P = 0.029-0.030). The individual allele of SNP5G, SNP6A, SNP7G, and SNP8T were associated with rapid decline in FEV1.0 (%predicted) [odds ratio (95% confidence interval) = 2.35 (1.194.65), P = 0.0141. The SNP5G/SNP6A/SNP7G/SNP8T haplotype was associated with an increased risk of deterioration of FEV(1.0)(%predicted) (P = 0.017). Importantly, SNP6 caused a change in amino acids in CDC6 protein (Val441 Ile), immediately upstream of the caspase-3-dependent cleavage site of CDC6 (Asp442) during apoptosis. These results suggest that CDC6 may be one of the susceptibility genes that contribute to rapid decline in lung function despite smoking cessation in these patients with COPD. (C) 2009 Elsevier Inc. All rights reserved.