title: A novel polymorphism in CDC6 is associated with the decline in lung function of ex-smokers in COPD.
abstract: 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 30months 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 FEV(1.0) (%predicted) [odds ratio (95% confidence interval)=2.35 (1.19-4.65), P=0.014]. 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 (Val441Ile), 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.
authors.affiliation: Department of Pulmonary Medicine, Tohoku Central Hospital, Wagocho, Yamagata, Japan. ntakabatake@tohoku-ctr-hsp.com
authors.forename: Noriaki
authors.initials: N
authors.lastname: Takabatake
authors.forename: Sayumi
authors.initials: S
authors.lastname: Toriyama
authors.forename: Akira
authors.initials: A
authors.lastname: Igarashi
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Tokairin
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Konta
authors.forename: Sumito
authors.initials: S
authors.lastname: Inoue
authors.forename: Shuichi
authors.initials: S
authors.lastname: Abe
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shibata
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D016540:Smoking Cessation
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins