Background

The identification of smoking-related lung disease in current and former smokers with normal FEV₁ is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV₁/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV₁/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group.

Methods

We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV₁ and FEV₁/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV₁/FVC criteria thresholds.

Results

The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV₁ and FEF_25-75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV₁/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality.

Conclusions

Ever-smokers with normal FEV₁ and FEV₁/FVC <  0.70 but > LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone.

Background

Electronic cigarettes (e-cigarettes) are battery-operated nicotine-delivery devices used by some smokers as a cessation tool as well as by never smokers.

Objective

To determine the usage of e-cigarettes in older adults at risk for or with chronic obstructive pulmonary disease (COPD).

Design

Prospective cohorts.

Participants

COPDGene (N = 3536) and SPIROMICS (N = 1060) subjects who were current or former smokers aged 45-80.

Main measures

Participants were surveyed to determine whether e-cigarette use was associated with longitudinal changes in COPD progression or smoking habits.

Key results

From 2010 to 2016, participants who had ever used e-cigarettes steadily increased to 12-16%, but from 2014 to 2016 current use was stable at ~5%. E-cigarette use in African-Americans (AA) and whites was similar; however, AA were 1.8-2.9 times as likely to use menthol-flavored e-cigarettes. Current e-cigarette and conventional cigarette users had higher nicotine dependence and consumed more nicotine than those who smoked only conventional cigarettes. E-cigarette users had a heavier conventional cigarette smoking history and worse respiratory health, were less likely to reduce or quit conventional cigarette smoking, had higher nicotine dependence, and were more likely to report chronic bronchitis and exacerbations. Ever e-cigarette users had more rapid decline in lung function, but this trend did not persist after adjustment for persistent conventional cigarette smoking.

Conclusions

E-cigarette use, which is common in adults with or at risk for COPD, was associated with worse pulmonary-related health outcomes, but not with cessation of smoking conventional cigarettes. Although this was an observational study, we find no evidence supporting the use of e-cigarettes as a harm reduction strategy among current smokers with or at risk for COPD.

Background

Chronic obstructive pulmonary disease (COPD) varies significantly in symptomatic and physiologic presentation. Identifying disease subtypes from molecular data, collected from easily accessible blood samples, can help stratify patients and guide disease management and treatment.

Methods

Blood gene expression measured by RNA-sequencing in the COPDGene Study was analyzed using a network perturbation analysis method. Each COPD sample was compared against a learned reference gene network to determine the part that is deregulated. Gene deregulation values were used to cluster the disease samples.

Results

The discovery set included 617 former smokers from COPDGene. Four distinct gene network subtypes are identified with significant differences in symptoms, exercise capacity and mortality. These clusters do not necessarily correspond with the levels of lung function impairment and are independently validated in two external cohorts: 769 former smokers from COPDGene and 431 former smokers in the Multi-Ethnic Study of Atherosclerosis (MESA). Additionally, we identify several genes that are significantly deregulated across these subtypes, including DSP and GSTM1, which have been previously associated with COPD through genome-wide association study (GWAS).

Conclusions

The identified subtypes differ in mortality and in their clinical and functional characteristics, underlining the need for multi-dimensional assessment potentially supplemented by selected markers of gene expression. The subtypes were consistent across cohorts and could be used for new patient stratification and disease prognosis.

Background

The aim of this study is to identify genetic loci associated with post-bronchodilator FEV₁/FVC and FEV₁, and develop a multi-gene predictive model for lung function in COPD.

Methods

Genome-wide association study (GWAS) of post-bronchodilator FEV₁/FVC and FEV₁ was performed in 1645 non-Hispanic White European descent smokers.

Results

A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV₁/FVC (p = 1.2 × 10^- 8) and FEV₁ (p = 2.1 × 10^- 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10^- 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV₁/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P <  2.2 × 10^- 16).

Conclusions

This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function. Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers. The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity. Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25-75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

Objective

We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.

Methods

We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.

Results

We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10^-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10^-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10^-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10^-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10^-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.

Conclusions

Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.