No abstract

Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86–58.82 and OR=16.90, 95% CI=2.09-142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

Previous studies have described that there are different types of disease in patients with established chronic obstructive pulmonary disease (COPD) with different clinical course and functional responses. The aim of this study was to evaluate if the presence of low transfer factor (LTF) values can predict the effectiveness of bronchodilator therapy, and to assess whether this group has different risk factors that may be related with the responses. Eighty patients with COPD were evaluated on three occasions. Initial assessment included a standard respiratory questionnaire, blood analysis, skin prick test and baseline lung function, all performed on the first visit. Bronchodilator response was evaluated after low (0.2 mg) and high (1 mg) doses of salbutamol, and after 2 weeks of oral prednisone. In patients with normal TLCO/VA % (NTF), a higher proportion of subjects with previous history of atopy was the only statistically significant difference compared to those with LTF (odds ratio 4.33; 95% confidence interval 1.06–25.15). Although the mean response in forced expiratory volume in 1 s (FEV₁) to treatment was analogous in both groups, when bronchodilation was expressed as percent of predicted, there was a clear trend to a lower response in patients with LTF (0.2 mg salbutamol: 6.99 ± 5.64 vs. 8.94 ± 6.61, p = 0.15; 1 mg salbutamol: 10.18 ± 6.37 vs. 13.45 ± 7.90, p < 0.05; oral prednisone: 5.51 ± 6.94 vs. 8.74 ± 10.81, p = 0.06). The percentage of patients who had >12% improvement from that predicted in FEV₁ was also lower in this group (42 vs. 72%; p < 0.05). Moreover, TLCO/VA% was significantly lower in those subjects with a negative bronchodilator trial with salbutamol (68 ± 25 vs. 81 ± 26; p < 0.05) and prednisone (69 ± 26 vs. 90 ± 22; p < 0.01). In patients with LTF and NTF, airway responsiveness was only significantly related with basal airflow limitation (LTF, r = 0.44; NTF, r = 0.38). All other interaction terms were not statistically significant. These results indicate that in patiens with similar serverity of COPD, the presence of LTF indicates a decreased probability of a positive bronchodilator response, probably reflecting different pathological lesions. We suggest that transfer factor should be taken into consideration when bronchial response is evaluated in large clinical trials.

Chronic obstructive pulmonary disease (COPD) is associated with impaired gas mixing and increased dead space, but little is known about the effect of improving alveolar gas sample by complete correction of dead space in an attempt to significantly improve the final result of transfer factor compared with standard guidelines of the European Respiratory Society (ERS) and American Thoracic Society (ATS). By using a rapid infrared analyzer, TLCO was measured by the single breath method in 152 COPD patients at different stages of severity (FΕV₁:57% predicted; CI 95%:24–91). Standard washout volume of 0.75 liter was insufficient to clear phases I and II in 36 patients (23.7%). In 19 subjects (12.5%), a washout volume larger than 1 liter was necessary for complete dead space clearance, although in these patients, correction visually adequate to complete clear phases I and II resulted in higher TLCO values. Only in 5 patients (3,3%) did the final result change by more than 5% from the previous value. A vital capacity higher than 3 liters, rather than the degree of airflow limitation was a better predictor for larger washout volume requirements. We conclude that in the measurement of TLCO by the breathholding method, ERS and ATS recommendations for washout volume can be safely used for clinical purposes in a wide range of patients with mild to severe obstruction.

Introduction: Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogeninduced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers. Methods: We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits. Results: Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL. Conclusions: Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases.