A single nucleotide polymorphism in the CCL1 gene predicts acute exacerbations in chronic obstructive pulmonary disease.
BACKGROUND
Acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality in COPD.


OBJECTIVE
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.


RESULTS
In the 2-yr retrospective study , one SNP (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/EBPbeta, 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.
Takabatake
Noriaki
N
First Department of Internal Medicine, Yamagata University School of Medicine. 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan. takabata@med.id.yamagata-u.ac.jp
Shibata
Yoko
Y
Abe
Shuichi
S
Wada
Toshihiro
T
Machiya
Jun-ichi
J
Igarashi
Akira
A
Tokairin
Yoshikane
Y
Ji
Guijin
G
Sato
Hidenori
H
Sata
Makoto
M
Takeishi
Yasuchika
Y
Emi
Mitsuru
M
Muramatsu
Masaaki
M
Kubota
Isao
I
D000368:Aged; D000483:Alleles; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000235:genetics*; D002630:Chemotactic Factors / Q000235:genetics; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012189:Retrospective Studies; D012720:Severity of Illness Index
C065971:CCL1 protein, human; D054402:Chemokine CCL1; D019742:Chemokines, CC; D002630:Chemotactic Factors; D004247:DNA