title: A single nucleotide polymorphism in the CCL1 gene predicts acute exacerbations in chronic obstructive pulmonary disease.
abstract: 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.
authors.affiliation: 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
authors.forename: Noriaki
authors.initials: N
authors.lastname: Takabatake
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shibata
authors.forename: Shuichi
authors.initials: S
authors.lastname: Abe
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wada
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Machiya
authors.forename: Akira
authors.initials: A
authors.lastname: Igarashi
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Tokairin
authors.forename: Guijin
authors.initials: G
authors.lastname: Ji
authors.forename: Hidenori
authors.initials: H
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Sata
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: 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
chemical_list: C065971:CCL1 protein, human; D054402:Chemokine CCL1; D019742:Chemokines, CC; D002630:Chemotactic Factors; D004247:DNA