The similar distribution of smoky coal exposure between COPD cases and controls indicates that there was a high exposure pattern in the study population. It means that COPD cases were exposed to a high level of IAP, and that IAP should be a strong risk factor if it was to be compared to the exposure pattern in the general population. The similar distributions of tobacco smoking in two comparison groups implies that smoking is not the driving risk factor for COPD as documented in the cross-sectional study (He and Yang, 1994
) and the cohort study (Chapman et al., 2005a
) in Xuan Wei, which is analogous to the case of lung cancer (He and Yang, 1994
), even though the sample size is small.
CSF2 is a mediator involved in the recruitment and activation of leucocytes including eosinophils and neutrophils, the latter of which is critical for COPD. Increased levels of CSF2 have been found in the epithelium and bronchoalveolar lavage fluid from subjects with chronic bronchitis and asthma (Balbi et al., 1997
). Inhibition of the cytokine results in a reduced influx of neutrophils and increased susceptibility to respiratory infections (Shibata et al., 2001
). The polymorphism at codon 117 of CSF2
encodes a nonconservative amino acid change, a hydrophilic (Thr) to a hydrophobic (Ile) amino acid, in a conserved and functionally important region. In contrast to Asian populations, the Thr allele is uncommon in Caucasians and was found to be a risk factor for atopic asthma in a Swiss population (Rohrbach et al., 1999b
). However, in our population the CSF2
117Ile allele was significantly associated with an increased risk of COPD, suggesting that it plays a different role in COPD and in atopic asthma. It is also possible that if the observed association is due to linkage disequilibrium with an unknown variant, the associations with risk may differ between ethnic populations due to different linkage disequilibrium patterns.
IL8 is a potent neutrophil chemoattractant that is involved in both inflammatory and non-inflammatory processes. The -351 substitution is located in the IL8
promoter region, which contains several binding sites for transcription factors and harbors an interferon-stimulated response element (Yamaoka et al., 2004
). In an in vitro assay, the IL8
–351A variant showed greater expression than the T allele with the highest values being observed for the AA genotype (Hull et al., 2000a
). The -351A variant was reported to be associated with an increased risk of respiratory syncytial virus (RSV) bronchiolitis (Hull et al., 2000c
). Although one study reported that the -351A variant was associated with a reduced risk of asthma (Heinzmann et al., 2004a
), this finding was not replicated in a larger Korean study (Park et al., 2004
). We observed an increased risk of COPD with the AA genotype, which is consistent with the functional data for the polymorphism and the association observed for RSV bronchiolitis. The association with IL8
–351A may be due to its linkage to another functional variant based on a haplotype analysis (Hull et al., 2001
). The tight linkage pattern through the 5′ region in our population supports the hypothesis and extensive haplotype analysis of IL8
is warranted to extend the finding.
It was reported that IL8 and CSF2 have synergistic effects in attracting neutrophils in the female reproductive tract (Shen et al., 2004
). Thus, we speculated that the CSF2
117Ile and IL8
-351A variants may have a synergistic effect on COPD risk through the assembling of more pro-inflammatory cells and the worsening of the ill-regulated inflammation process. Although our p-value for interaction was not significant, we found that individuals carrying at least one at-risk allele in both genes had a significantly higher risk of COPD than individuals carrying no at-risk alleles.
Our study is limited by relatively small sample size, and the possibility of false positive findings cannot be excluded. Nonetheless, our study, like others, suggests that genetic variation in CSF2 and IL8 is important in the pathogenesis of COPD. With the specific exposure pattern in our population, the polymorphisms in CSF2 and IL8 may be important for the development of COPD among populations with high exposure to IAP. These results should be replicated in larger studies, both in subjects with high air pollution exposure and in the general population.