Abstract
BackgroundUnderstanding the environmental and genetic risk factors of accelerated lung function decline in the general population is a first step in a prevention strategy against the worldwide increasing respiratory pathology of chronic obstructive pulmonary disease (COPD). Deficiency in antioxidative and detoxifying Glutathione S-transferase (GST) gene has been associated with poorer lung function in children, smokers and patients with respiratory diseases. In the present study, we assessed whether low activity variants in GST genes are also associated with accelerated lung function decline in the general adult population.MethodsWe examined with multiple regression analysis the association of polymorphisms in GSTM1, GSTT1 and GSTP1 genes with annual decline in FEV1, FVC, and FEF25–75 during 11 years of follow-up in 4686 subjects of the prospective SAPALDIA cohort representative of the Swiss general population. Effect modification by smoking, gender, bronchial hyperresponisveness and age was studied.ResultsThe associations of GST genotypes with FEV1, FVC, and FEF25–75 were comparable in direction, but most consistent for FEV1. GSTT1 homozygous gene deletion alone or in combination with GSTM1 homozygous gene deletion was associated with excess decline in FEV1 in men, but not women, irrespective of smoking status. The additional mean annual decline in FEV1 in men with GSTT1 and concurrent GSTM1 gene deletion was -8.3 ml/yr (95% confidence interval: -12.6 to -3.9) relative to men without these gene deletions. The GSTT1 effect on the FEV1 decline comparable to the observed difference in FEV1 decline between never and persistent smoking men. Effect modification by gender was statistically significant.ConclusionOur results suggest that genetic GSTT1 deficiency is a prevalent and strong determinant of accelerated lung function decline in the male general population.
Highlights
Understanding the environmental and genetic risk factors of accelerated lung function decline in the general population is a first step in a prevention strategy against the worldwide increasing respiratory pathology of chronic obstructive pulmonary disease (COPD)
GSTM1 and GSTT1 null genotypes were present in 53% and 18% of all subjects
The homozygous GSTP1 Val/Val genotype was present in 9.4% and its allele distribution was in HardyWeinberg equilibrium
Summary
Understanding the environmental and genetic risk factors of accelerated lung function decline in the general population is a first step in a prevention strategy against the worldwide increasing respiratory pathology of chronic obstructive pulmonary disease (COPD). Several lines of evidence point to the involvement of the supergene family of glutathione Stransferase (GST) in respiratory disease etiology, including that of COPD Given their function in the metabolism of environmental toxicants as well as in the inactivation of reactive oxygen species, these genes represent promising candidates for modification of the susceptibility to tobacco-smoke derived and other inhaled irritants [14,15]. Two prevalent homozygous gene deletions of the Mu-1 and Theta-1 GST members (GSTM1 and GSTT1) have repeatedly been associated with increased susceptibility to respiratory disease and lung function deficits in children, asthmatics, and smokers with respiratory symptoms [16,17,18,19,20] It is, unknown whether these GST polymorphisms influence lung function in the general population. We investigated the association of the three most studied GST polymorphisms (GSTM1 and GSTT1 gene deletions and GSTP1 Ile105Val single nucleotide polymorphism) with change in lung function over an eleven year follow-up using the population-based SAPALDIA cohort (Swiss Cohort Study on Air Pollutants and Lung and Heart Diseases in Adults) and hypothesized that low-activity variants would accelerate lung function decline in the general adult population
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