This study selected randomized samples of subjects of the same sex and race. The mean age of the subjects and their smoking index were statistically matched. All subjects were of Caucasian origin; it was found that the frequency of an allele can vary in different racial groups [3
The mean values of the post-bronchodilator FEV1, FEV1/FVC and FEF25/75% of predicted showed significant negative correlations with age and were significantly reduced in COPD patients compared to non-COPD groups (p < 0.0001).
Our subjects had a heavy smoking history of more than 20 pack years. Mean values of the post-bronchodilator FEV1, FEV1/FVC% of predicted had significant negative correlations with their smoking history.
Adenovirus C infects more than 80% of the human population early in life [20
]. Moreover, nearly 100% of adults have serum antibody to multiple serotypes – a finding indicating that infection is common in childhood [21
In a study that included 60 children presenting with recurrent upper and/or lower respiratory tract infection done in the National Research Centre of Egypt, it was demonstrated that passive cigarette smoking remains an enormous health problem and is a principal cause of recurrence of respiratory infections in children, mainly adenovirus C infection. High prevalence and persistence of adenovirus C infection, exceeding 96% of cases, were demonstrated in children by positive serum IgG and documented by latent gene expression [22
In our study, identification of adenovirus C in COPD and non-COPD subjects demonstrated the persistence of latent infection during childhood and confirmed our previous study in children. Although cigarette smoking is the major risk factor for the development of COPD, only 15% to 20% of all smokers develop airway obstruction [23
]. Therefore, adenovirus that remains from a previous infection of the lungs in a smoker may enhance the inflammatory process in their lungs [24
]. The correlation between adenovirus C, COPD and deterioration of pulmonary function was not demonstrated in this study, because all included subjects were positive for adenovirus C and genotyping was not done.
Latent adenoviral infection contributes to chronic airway inflammation through E1A-dependent NF-κB (nuclear factor-κβ) activation. It was found that E1A regulation of the lipopolysaccharide (LPS) response may play a role in acute exacerbations as a consequence of bacterial infections in COPD. Adenovirus E1A 13S (adenovirus early gene product) stimulates the TNF gene in inflammatory cell lines. Moreover, it could contribute to airway remodeling in COPD by the viral E1A gene, inducing transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) expression and shifting cells to a more mesenchymal phenotype [25
The TNF-α mediated inflammation is thought to play a key role in both the respiratory and systemic features of COPD. Single nucleotide polymorphism (SNP) in the promoter region of the TNF-α gene (G→A at position –308) directly affects gene regulation, and is associated with high TNF-α production [26
In the present study, the genotype distribution of TNF-α –308 polymorphism in Caucasian populations was heterozygous G/A in 13 cases (11.3%) and homozygous A in 102 cases (88.7%). Homozygous alleles G/G were not detected in the studied groups. The TNF-α –308A allele frequency ranged from 10% [27
] to 17% [28
] in the white population, and from 5% [9
] to 8% [6
] in the Asian population. The possible cause of this discrepancy may be an ethnic difference affecting prevalence.
The study demonstrated no statistically significant difference between the 3 groups in the distribution of homozygous A genotype. The heterozygous G/A was present in a higher percentage in the resistant smoker group compared to the other groups, with no statistically significant difference between them. These results were in accordance with several studies that fail to find an association between COPD and TNF-α –308G/A polymorphism in Caucasians [27
], which might be explained by variation in genotype frequencies between races, or by linkage disequilibrium with HLA alleles, seen previously in the Caucasian population [33
In contrast to these studies on white subjects, two studies on Asian subjects showed an association of TNF-α –308G/A polymorphism and COPD [6
]. Alternatively, the allele could be in linkage disequilibrium with another gene that increases susceptibility to COPD in smokers only in the Asian population [34
On the other hand, the homogenous A genotype in COPD patients in the current study was accompanied by a statistically significant reduction in the mean values of the post-bronchodilator FEV1
/FVC and FEF25/75% of predicted compared to heterozygous G/A genotypes in COPD (p
< 0.05). Our findings agreed with those of Keatings et al
], who demonstrated that homozygosity for the A allele predisposes to a worse prognosis for COPD.
The surfactant proteins are hydrophobic proteins that contribute to regulation of surface tension in the alveoli. Components of surfactant also have a role in host defense and control of inflammation. Alterations of surfactant might therefore be a factor in COPD [26
The genotype distribution of the SP-B +1580 C/T gene polymorphism showed that the non-smokers had a higher frequency of the heterozygous C/T genotype compared to either resistant smokers or COPD patients. Meanwhile, resistant smokers had a significantly higher frequency of T/T genotype, and C/C genotype was higher in COPD patients (p = 0.005). The allelic variation of SP-B +1580 between smokers (C/C and T/T) and non-smokers (C/T) indicates that these alleles appeared to be “smoking-dependent”. Moreover, the homozygous alleles (C/C and T/T) were associated with significant impairment of pulmonary function in the COPD group compared to that in the heterozygous alleles (C/T).
In contrast to our findings, Guo et al
] in a Mexican population with COPD reported that the frequency of the homozygous alleles C/C represented 49% of cases and the heterozygous alleles C/T represented 76% of cases. When both marker alleles were present, the odds ratio (OR) for COPD was considerably increased (OR = 24.3, p
< 0.001) compared to when both markers were absent. No significant differences were observed when one marker was present and the other was absent (OR for T
= 0.73, p
= 0.81; OR for C
= 1.9, p
In a study done in a Chinese Han population, it was concluded that the SP-B 1580 T allele was probably associated with increased susceptibility to COPD [36
In spite of the difference in the distribution of allelic markers between populations, probably due to ethnic variation, all studies agreed that SP-B+1580 C/T is a smoking-dependent gene which plays a role in COPD and that the T allele is associated with deterioration of pulmonary functions. But in the present study, SP-B homozygous alleles (either C/C or T/T) were found to be associated with worse prognosis of COPD.
Studies in transgenic mice have shown that the targeted expression of IL-13 in the adult lung causes emphysema, mucus metaplasia, and inflammation that mirror, in many ways, the lesions seen in human COPD. The IL-13 may play an important role in the pathogenesis of COPD, particularly in patients with asthma-like features [11
The distribution of the genotype of IL-13 –1055 C/T polymorphism showed no significant difference between the studied groups although there was a higher frequency of homozygous T genotype in the COPD patient group compared to other groups. Also, the homozygous T and heterozygous C/T genotypes were associated with a significant reduction in the mean values of the post-bronchodilator FEF25/75% of predicted compared to that in the case of homozygous C genotype in the COPD group (p = 0.001). These results indicate that the T allele is associated with COPD and deterioration of pulmonary functions.
Our results are in accordance with those of van der Pouw Kraan et al
., who demonstrated that IL-13 promoter region polymorphism –1055 C→T, associated with increased IL-13 production, is more common in COPD patients [12
In conclusion, from our results we concluded that COPD is a disease caused by the interaction of combined genes and environmental influences. In the presence of smoking and latent adenovirus C infection, TNF-α –308G/A, SP-B+1580 C/T and IL-13 –1055 C/T gene polymorphisms predispose to the development of COPD and decline of lung functions.