Neither of the two restrictions did essentially alter the results

Neither of the two restrictions did essentially alter the results (Table S1). Replacing the change of FEF25-75% by the change of the ratio FEF25-75%/FVC led to very similar conclusions (Table S2). Finally, 17-AAG in order to detect potential participation bias, we weighted each observation inverse to the probability of being included in the study sample. None of the results of the regression analyses did materially change (Table S3). Discussion In the present study, neither PiS nor PiZ heterozygosity influenced longitudinal lung function measured by ��FEV1 or ��FVC, independent of smoking or obesity status. However, PiMZ genotype was associated with an accelerated FEF25-75% decline in smoking and obesity subgroups from the general population.

Results for participants in the upper tertile of hs-CRP values strengthened the notion that PiMZ carriers might be more susceptible to systemic pro-inflammatory conditions with respect to lung function parameters indicating narrowing of small airways. The Role of Smoking and Pulmonary Oxidative Stress It is well established that smokers suffering from severe AAT deficiency, a condition accompanied by only 15% of normal AAT blood concentrations, are particularly vulnerable to developing early onset COPD [2]. There is less evidence that intermediate or even mild AAT deficiency modify the effect of smoking or other oxidative inhalants on lung function. In a small study of 56-year-old men, a higher mean annual decrease in FEV1 in smoking PiMZ individuals was reported as compared with non-smoking PiMZ or smoking PiMM individuals [17], but larger studies could not find such an interaction [7], [9].

Results of studies investigating the impact of environmental and occupational exposure are heterogeneous [18]. Passive smoking has been shown in school children to be associated with cross-sectional lower lung function only in children having low levels of AAT in the blood, and particularly in measures of mid- to end-expiratory flow rates [19]. A recent longitudinal study found accelerated lung function declines in New York City firefighters of PiMZ genotype compared to PiMM in the years after World Trade Center collapse accompanied by massive air pollution, and no such difference could be observed prior to September 11, 2001 [20]. Support for a gene-environment interaction comes also from genome-wide as well as from experimental studies.

While genome-wide association studies on COPD and lung function have not found the SERPINA1 locus among the top hit signals [21], [22], [23], it was the most strongly associated candidate GSK-3 gene in ever smokers in a comprehensive evaluation of potential lung function associated genes in more than 20,000 individuals from the general population [24]. Oxidation of the Z form by cigarette smoke induced its polymerization in lung tissue of transgenic PiZZ mice [12].

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