A novel polymorphism in CDC6 is associated with the decline in lung function of ex-smokers in COPD.
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.
Takabatake
Noriaki
N
Department of Pulmonary Medicine, Tohoku Central Hospital, Wagocho, Yamagata, Japan. ntakabatake@tohoku-ctr-hsp.com
Toriyama
Sayumi
S
Igarashi
Akira
A
Tokairin
Yoshikane
Y
Takeishi
Yasuchika
Y
Konta
Tsuneo
T
Inoue
Sumito
S
Abe
Shuichi
S
Shibata
Yoko
Y
Kubota
Isao
I
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
C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins