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2.  The Impact of Nonlinear Smoking Effects on the Identification of Gene-by-Smoking Interactions in COPD Genetics Studies 
Thorax  2010;66(10):903-909.
Background
The identification of gene-by-environment interactions is important to understand the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and FEV1; however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.
Methods
We examined the relationship between FEV1 and pack-years of smoking exposure in 4 large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, we compared the accuracy and power of two different approaches to model smoking by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.
Results
We identified nonlinear relationships between smoking and FEV1 in 4 large cohorts. We demonstrated that in most situations where the relationship between pack-years and FEV1 is nonlinear, a piecewise-linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. We applied the piecewise linear approach to a genetic association analysis of the PI*Z allele in the Norway case-control cohort and identified a potential PI*Z-by-smoking interaction (p=0.03 for FEV1 analysis, p= 0.01 for COPD susceptibility analysis).
Conclusion
In study samples with subjects having a wide range of COPD severity, a nonlinear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this nonlinearity can be more powerful and less-biased than the commonly-used approach of using total pack-years to model the smoking effect.
doi:10.1136/thx.2010.146118
PMCID: PMC3312798  PMID: 21163806
smoking; FEV1; gene-by-environment interaction; COPD; gene
3.  Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ-1 
Rationale: Oxidative stress is a key contributor in chronic obstructive pulmonary disease (COPD) pathogenesis caused by cigarette smoking. NRF2, a redox-sensitive transcription factor, dissociates from its inhibitor, KEAP1, to induce antioxidant expression that inhibits oxidative stress.
Objectives: To determine the link between severity of COPD, oxidative stress, and NRF2-dependent antioxidant levels in the peripheral lung tissue of patients with COPD.
Methods: We assessed the expression of NRF2, NRF2-dependent antioxidants, regulators of NRF2 activity, and oxidative damage in non-COPD (smokers and former smokers) and smoker COPD lungs (mild and advanced). Cigarette smoke–exposed human lung epithelial cells (Beas2B) and mice were used to understand the mechanisms.
Measurements and Main Results: When compared with non-COPD lungs, the COPD patient lungs showed (1) marked decline in NRF2-dependent antioxidants and glutathione levels, (2) increased oxidative stress markers, (3) significant decrease in NRF2 protein with no change in NRF2 mRNA levels, and (4) similar KEAP1 but significantly decreased DJ-1 levels (a protein that stabilizes NRF2 protein by impairing KEAP1-dependent proteasomal degradation of NRF2). Exposure of Bea2B cells to cigarette smoke caused oxidative modification and enhanced proteasomal degradation of DJ-1 protein. Disruption of DJ-1 in mouse lungs, mouse embryonic fibroblasts, and Beas2B cells lowered NRF2 protein stability and impaired antioxidant induction in response to cigarette smoke. Interestingly, targeting KEAP1 by siRNA or the small-molecule activator sulforaphane restored induction of NRF2-dependent antioxidants in DJ-1–disrupted cells in response to cigarette smoke.
Conclusions: NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD.
doi:10.1164/rccm.200803-380OC
PMCID: PMC2542433  PMID: 18556627
chronic obstructive pulmonary disease; NRF2; DJ-1; oxidative stress; antioxidants
4.  Survival after Lung Volume Reduction in Chronic Obstructive Pulmonary Disease 
Rationale: COPD is associated with reduced life expectancy.
Objectives: To determine the association between small airway pathology and long-term survival after lung volume reduction in chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology.
Methods: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathology was assessed by comparing treated and untreated groups.
Measurements and Main Results: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55–6.92; P = 0.002). There was a trend toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically significant difference between the control and oral ± inhaled corticosteroid–treated groups (P = 0.019). However, corticosteroid treatment had no effect on airway wall thickening or luminal occlusion.
Conclusions: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion.
doi:10.1164/rccm.200612-1772OC
PMCID: PMC1976540  PMID: 17556723
premature death in COPD; airway remodeling; mucosal immune response; corticosteroids
5.  Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease 
Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury.
Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease.
Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype.
Measurements and Main Results: A total of 440 subjects with CF participated in the study (51% male; mean [± SD] age, 26 ± 11 yr; mean FEV1, 62 ± 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001).
Conclusions: In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity.
doi:10.1164/rccm.200508-1281OC
PMCID: PMC2648118  PMID: 16690975
CFTR genotype; glutathione; modifier genes

Results 1-5 (5)