Bowler, Russell P

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Rationale Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (>3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1–3. Conclusions Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.

Abstract Rationale Increased risk of coronavirus disease (COVID-19) hospitalization and death has been reported among patients with clinical lung disease. Objectives To test the association of objective measures of prepandemic lung function and structure with COVID-19 outcomes in U.S. adults. Methods Prepandemic obstruction (FEV1/FVC < 0.70) and restriction (FEV1/FVC ⩾ 0.7, FVC < 80%) were defined based on the most recent spirometry exam conducted in 11 prospective U.S. general population–based cohorts. Severe obstruction was classified by FEV1 < 50%. Percentage emphysema, percentage high-attenuation areas, and interstitial lung abnormalities were defined on computed tomography in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020 to 2023 and classified as severe (hospitalized or fatal) or nonsevere. Cause-specific hazard models were adjusted for sociodemographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status. Measurements and Main Results Among 29,323 participants (mean age, 67 yr), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs. normal; adjusted hazard ratio [aHR], 2.11; 95% confidence interval [CI], 1.02–1.27), restriction (vs. normal; aHR, 1.40; 95% CI, 1.12–1.76), and percentage emphysema (highest vs. lowest quartile; aHR, 1.64; 95% CI, 1.03–2.61), but not greater high-attenuation areas or interstitial lung abnormalities. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease. Conclusions Prepandemic severe spirometric obstruction, spirometric restriction, and greater percentage emphysema lung on computed tomography were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses.

Abstract Rationale Among tobacco-exposed persons with preserved spirometry (TEPSs), we previously demonstrated that different lung volume indices—specifically, elevated total lung capacity (TLC) versus elevated ratio of functional residual capacity to TLC (FRC/TLC)—identify different lung disease characteristics in the COPDGene cohort. Objective We sought to determine differential disease characteristics and trajectories associated with lung volume indices among TEPSs in the SPIROMICS cohort. Methods We categorized TEPSs (n = 814) by tertiles (low, intermediate, and high) of TLC or residual volume–to-TLC ratio (RV/TLC) derived from baseline computed tomography images and then examined clinical and spirometric disease trajectories in mutually exclusive categories of participants with high TLC without high RV/TLC ([TLC]high) versus high RV/TLC without high TLC ([RV/TLC]high). We examined differences in computed tomography–measured emphysema (Hounsfield units [HU] ⩽−950; parametric response mapping [PRM] of emphysema), air trapping (HU⩽−856; PRM of functional small airway disease; a disease probability measure for non-emphysematous gas trapping), airway geometry (the mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), respiratory symptoms (on the modified Medical Research Council Dyspnea Scale; COPD Assessment Test [CAT]; St. George’s Respiratory Questionnaire [SGRQ]; and Short Form-12 [SF12]), and outcomes (annualized exacerbation rate) between the two categories at baseline and over follow-up time up to 8.5 years, using regression modeling adjusted for age, sex, height, weight, and smoking status (current vs. former smoker) and burden (pack-years). Results In TEPSs, the pattern of spirometric disease progression differed between participants with [TLC]high and those with [RV/TLC]high: There was increased forced vital capacity with stable forced expiratory volume in 1 second in participants with [TLC]high, versus unchanged forced vital capacity but nominally decreased forced expiratory volume in 1 second in those with [RV/TLC]high. Compared with participants with [TLC]high, TEPSs with [RV/TLC]high had less emphysema (by HU ⩽−950) but more airway disease (by HU ⩽−856; PRM of functional small airway disease; disease probability measure for gas trapping, and mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), more respiratory symptoms (on the modified Medical Research Council Dyspnea Scale, CAT, SGRQ, and SF12), and more severe exacerbations at baseline. Over an average follow-up of 4.1 ± 2.4 years (range = 0.5–8.5 yr), TEPSs with [RV/TLC]high also had a higher likelihood of developing more severe spirometric disease (preserved ratio impaired spirometry or Global Initiative for Chronic Obstructive Lung Disease Classification 2) and worsening of their respiratory symptoms (on the CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not significantly different between the two categories over the follow-up period, TEPSs with [RV/TLC]high were more likely to have been prescribed a respiratory inhaler at their last follow-up visit. Conclusions In these TEPSs from the SPIROMICS cohort, lung volume stratification by TLC versus RV/TLC identifies two pre-COPD phenotypes with distinct respiratory symptoms, radiographic features, and clinical trajectories. The characteristics of these pre-COPD phenotypes match those previously described in the COPDGene cohort using TLC versus FRC/TLC stratification.

Abstract Rationale Ground-glass opacities (GGOs) in the absence of interstitial lung disease are understudied. Objectives To assess the association of GGOs with white blood cells (WBCs) and progression of quantified chest computed tomography emphysema. Methods We analyzed data of participants in the SPIROMICS study (Subpopulations and Intermediate Outcome Measures in COPD Study). Chest radiologists and pulmonologists labeled regions of the lung as GGOs, and the adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGOs (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBCs, changes in percentage emphysema, and clinical outcomes. Measurements and Main Results Among 2,714 participants, 1,680 had chronic obstructive pulmonary disease (COPD) and 1,034 had normal spirometry. Among participants with COPD, on the basis of multivariable analysis, current smoking and chronic productive cough were associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBC and neutrophil concentrations. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at 1-year follow-up visit by 11.7% (relative increase; 95% confidence interval, 7.5–16.1%; P < 0.001). We found no association between %GGOAMFM and 1-year FEV1 decline, but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up of 1,544 days (interquartile interval, 1,118–2,059). Among normal spirometry participants, we found similar results, except that %GGOAMFM was associated with progression to COPD at 1-year follow-up. Conclusions Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.

Abstract Rationale Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n = 1,367) versus above 4,000 ft (1,219 m) elevation (n = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (−32.3 m [95% confidence interval, −49.8 to −14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George’s Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT 01969344).