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BackgroundThe identification of gene-by-environment interactions is important for understanding 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 forced expiratory volume in 1 s (FEV1); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.MethodsThe relationship between FEV1 and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.ResultsNon-linear relationships between smoking and FEV1 were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV1 is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case–Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV1 analysis, p=0.01 for COPD susceptibility analysis).ConclusionIn study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.

Data from a controlled trial of asthma treatment that enrolled patients in the first decade of life were combined with follow-up data to provide novel information on the growth and decline in lung function in the first three decades of life in patients with asthma. In persons without lung disease, forced expiratory volume in 1 second (FEV 1 ) reaches its maximal level in late adolescence or early adulthood and remains stable for several years, a period known as the plateau of lung function, before gradually declining thereafter (Figure 1). 1 Under the construct described by Speizer and Tager, 1 the pattern of FEV 1 growth and decline in childhood and early adulthood is an important determinant of lung function in later adulthood; both reduced growth resulting in a low maximal level of lung function and early decline are associated with the subsequent development of chronic airflow . . .

Introduction: While airway inflammation in COPD is usually characterized by predominantly neutrophil driven processes, increasing evidence suggests that blood eosinophil levels are related to disease phenotypes and treatment response. Conclusion: Peripheral blood eosinophilia defined by a higher cutoff (200/ul or 4%) in COPD subjects is associated with an increased exacerbation rate.

Corresponding author's email: jhyun@partners.org Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with inflammation in the lung, and increasing evidence suggests systemic inflammation is an important mechanism underlying extrapulmonary manifestations of COPD. Conclusion: RNA-Seq profile of peripheral blood shows that genes associated with pulmonary phenotypes in COPD are mostly driven by cellular composition, while systemic phenotypes are characterized by gene expression changes that are independent of white blood cell proportions.

Corresponding author's email: rempa@channing.harvard.edu Background: Genome-wide association studies (GWAS) have identified numerous variants associated with chronic obstructive pulmonary disease (COPD), most of which are located in non-coding regions of the genome. Methods: To assess allelic imbalances in COPD candidate genes, we combined imputed genotyping data and whole-blood RNA sequencing data from 311 individuals in the COPDGene study, an observational study including Non-Hispanic White and African American smokers with and without COPD.

Rationale: The COPDGene study employs both quantitative CT scans that measure initial chronic obstructive pulmonary disease (COPD) and pulmonary function tests (PFT) by spirometry that measure the resultant physiologic changes in COPD. Methods: There were 7394 COPDGene participants (5316 non-Hispanic whites and 2078 African-Americans; 47% female) with complete disease axes and mortality data.

Results: Integration of LHE GWAS results with cell-type epigenomic annotations demonstrated enrichment in a broad range of cell types, including fetal lung cells (permutation p <0.001), IMR90 fibroblasts (p=0.005), CD3+ T-cells and CD14+ monocytes from peripheral blood (p=0.02 for both). Conclusions: Integrative genomic analysis implicates a wide range of cell types as mediators of genetic variation on emphysema development, with the strongest results found for fetal lung cells and fibroblasts, as well as T-cells and monocytes. eQTL colocalization identified 157 genes likely to be regulated by a causal variant responsible for both the GWAS and eQTL association.

Rationale: Upper lobe predominant emphysema is an important predictor of response to lung volume reduction surgery. [...]Genomic Annotation Shifter (GoShifter) analyses were carried out to identify overlap of trait-associated SNPs with DNase-I hypersensitive sites (DHS), transcription factor-binding sites (TFBS), and enhancer marks in 126 cell types from the Roadmap Epigenomics Project.