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A Single Nucleotide Polymorphism in the CCL1 Gene Predicts Acute Exacerbations in Chronic Obstructive Pulmonary Disease

First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata; HuBit Genomix, Inc., Tokyo; and Medical Research Institute, Tokyo Medical & Dental University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Noriaki Takabatake, M.D., First Department of Internal Medicine, Yamagata University School of Medicine. 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan. E-mail: takabata{at}med.id.yamagata-u.ac.jp

Rationale: Acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality in COPD.

Objectives: 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.

Measurements and Main 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/EBP, 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.

Key Words: acute exacerbations • C/EBP&beta • • chronic obstructive pulmonary disease • inflammatory chemokine • single nucleotide polymorphisms

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