Jørgen Vestbo

An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies

Background The 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. Methods The 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. Results Non-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). Conclusion In 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.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

RATIONALE Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES To identify coding variants associated with COPD. METHODS We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

S113 The effect of small airways disease and emphysema on the association between smoking and lung function, and bronchodilator response

Introduction and objectives The airflow limitation of COPD results from small airway disease and emphysema. These phenotypes are likely to have independent genetic risk factors. It is not known if the heterogeneity of COPD accounts for the relatively weak association between pack-years smoked and forced expiratory volume in 1 s (FEV1) seen within smoking populations, or bronchodilator response (BDR). This study aimed to assess the effect of these phenotypes on the association between smoking and FEV1 and on BDR. Method The international COPD genetics network is a multi-centre study aimed at identifying genes that predispose to COPD, in which high resolution computed tomography (HRCT) was used to quantify components of the COPD phenotype: (i) emphysema detected by radiologists (RE), (ii) emphysema assessed as per cent low-attenuation area (%LAA) and (iii) airway wall thickness (AWT) for airways with an internal perimeter of 10 mm (Pi10), 20 mm (Pi20), and average per cent wall area (WA%). They were then assessed for their effect on the association between smoking and lung function (FEV1% predicted (FEV1%)), and on BDR. Results RE data were available for 1159 individuals, 745 had complete data for Pi10, Pi20, AWT% and %LAA. The association between pack-years smoked and FEV1% was greater in those without (r=−0.41), compared to those with, RE (r=−0.12, p<0.001 for difference in effect). AWT and RE correlated with FEV1% but had different relationships with smoking; AWT was positively associated with pack-years but there was no relationship between RE severity and pack-years smoked. RE, %LAA and AWT made independent contributions to FEV1%. Post-bronchodilator increase in FEV1 was inversely associated with severity of RE (Abstract S113 Table 1), even after adjustment for pre-bronchodilator FEV1 (p<0.01). BDR was also inversely associated with %LAA (p=0.02, and p≤0.05 adjusted for baseline FEV1).Abstract S113 Table 1 Severity of RE Mild (5–25%) Moderate (25–50%) Severe (>50%) p (trend) Number 228 185 266 – BDR, FEV1 (mls) 171.3±188.2 134.4±174.7 100.2±129.6 ≤0.0001 Conclusion The AWT component of COPD, but not the severity of RE, increases with pack-years smoked, and the association between pack-years and FEV1% is greatest in those with an airway predominant phenotype. This suggests different gene-smoking interactions between phenotypes. RE and %LAA independently contribute to FEV1% and therefore measure different components of emphysema, however both were inversely associated with BDR.