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Rebecca Baqiyyah Conway,1 Katherine A Pratte,2 Russell Paul Bowler,3 Kendra A Young,1 Gregory l Kinney,1 Erin Austin,4 Yisha Li,1 Donald McClain,5 John Hokanson,1 James D Crapo6 1Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA; 2Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO, 80206, USA; 3Department of Genomic Sciences, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA; 4Department of Mathematical and Statistical Sciences, Denver, University of Colorado, Denver, CO, 80204, USA; 5Section of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC, USA; 6Department of Medicine, National Jewish Health, Denver, CO, 80206, USACorrespondence: Rebecca Baqiyyah Conway, Department of Epidemiology, University of Colorado, Anschutz Medical Campus, 13001 East 17th Place, Mail Stop B119, Aurora, CO, 80045, USA, Email rebecca.conway@cuanschutz.eduBackground: Little information is available on iron with diabetes risk among African Americans, a population where both anemia and elevated ferritin are common. We tested whether plasma proteomic measurements of ferritin and transferrin were associated with increased diabetes risk in a cohort of current and former African American (NHB) and Non-Hispanic White (NHW) smokers.Methods: NHB and NHW participants from the COPDGene study who were free of diabetes (n = 4693) at baseline were followed for incident diabetes. The SomaScan was used to determine the relative amounts of natural log-transformed ferritin, transferrin, and hepcidin.Findings: During an average of 5.6 years of follow-up, diabetes incidence was 7.9%. Ferritin at follow-up was higher in NHB than NHW participants (p = < 0.0001). Ferritin at follow-up was associated with increased diabetes risk (OR = 1.36, 95% CI = 1.08– 1.70), while transferrin was associated with decreased risk (OR = 0.25, 95% CI = 0.08– 0.77) controlling for age, sex, BMI, smoking pack-years, hepcidin, CRP, and Il-6. Race-specifically, increased risk associated with higher ferritin levels among NHB (OR = 1.56, 95% CI = 1.13– 2.16) but not NHW (OR = 1.22, 95% CI = 0.89– 1.68) participants. Sex-specifically, ferritin’s relationship was similar among NHB men and women and NHW women (ORs ranging from 1.41– 1.59); but not NHW men (OR = 0.98, 95% CI = 0.64– 1.49). Similarly, transferrin ORs non-significantly ranged from 0.19– 0.30 for NHB men and women and NHW women, but was significant for NHW men (OR = 0.07, 95% CI = 0.01– 0.63).Interpretation: Higher body iron stores is associated with increased diabetes risk among both NHB and NHW people. Unsuspected elevated iron stores may increase diabetes risk in NHB patients and should be monitored.Keywords: diabetes, iron, ferritin, transferrin, African Americans

Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Robert P Young1,4, Raewyn J Hopkins1, Gregory D Gamble1, Carol Etzel2, Randa El-Zein2, James D Crapo31Department of Medicine and School of Biological Sciences, University of Auckland, Auckland, New Zealand; 2Department of Epidemiology, UT MD Anderson Cancer Center, Houston, TX, USA; 3National Jewish Health, Denver, CO, USA; 4Synergenz Biosciences Ltd, Auckland, New ZealandAbstract: Epidemiological studies indicate that tobacco smoke exposure accounts for nearly 90% of cases of chronic obstructive pulmonary disease (COPD) and lung cancer. However, genetic factors may explain why 10%–30% of smokers develop these complications. This perspective reviews the evidence suggesting that COPD is closely linked to susceptibility to lung cancer and outlines the potential relevance of this observation. Epidemiological studies show that COPD is the single most important risk factor for lung cancer among smokers and predates lung cancer in up to 80% of cases. Genome-wide association studies of lung cancer, lung function, and COPD have identified a number of overlapping “susceptibility” loci. With stringent phenotyping, it has recently been shown that several of these overlapping loci are independently associated with both COPD and lung cancer. These loci implicate genes underlying pulmonary inflammation and apoptotic processes mediated by the bronchial epithelium, and link COPD with lung cancer at a molecular genetic level. It is currently possible to derive risk models for lung cancer that incorporate lung cancer-specific genetic variants, recently identified “COPD-related” genetic variants, and clinical variables. Early studies suggest that single nucleotide polymorphism-based risk stratification of smokers might help better target novel prevention and early diagnostic strategies in lung cancer.Keywords: lung cancer, chronic obstructive pulmonary disease, association study, single nucleotide polymorphism, risk model

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD. [ABSTRACT FROM AUTHOR]

Rationale: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function.Objective: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term = 185 d).Methods: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured.Measurements and Main Results: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity.Conclusions: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants. [ABSTRACT FROM AUTHOR]

Rationale: Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in controlling oxidant-mediated stress and inflammation. High levels of EC-SOD are found in the lung. Acute lung injury (ALI) frequently occurs in patients with infection, and levels of EC-SOD have been shown to modulate severity of lung injury in transgenic animal models of endotoxemia-induced ALI. An R213G single nucleotide polymorphism (SNP) has been shown to alter levels of EC-SOD and patient outcomes in chronic obstructive pulmonary disease (COPD) and ischemic heart disease.Objectives: To determine genetic variation in the promoter and EC-SOD gene and to examine whether EC-SOD haplotype blocks are associated with clinical outcomes.Methods: We sequenced the EC-SOD promoter and gene to determine genetic variation and linkage disequilibrium (LD) patterns in a European American population. Two separate patient populations with infection-associated ALI were also evaluated to determine whether EC-SOD haplotypes were associated with clinical outcomes.Measurements and Main Results: Sequencing resulted in the identification of 28 SNPs with relatively strong LD and 1 block consisting of 4691-5321-5360-5955-5982. This specific block was shown to be protective in two separate patient populations with infection associated ALI. In particular, patients with a GCCT haplotype had a reduced risk of time on the ventilator and mortality.Conclusions: These results indicate that a GCCT haplotype may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI. [ABSTRACT FROM AUTHOR]

Rationale: Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen I, hyaluronan, and heparan sulfate. Inherited change in SOD3 expression or function could affect lung matrix homeostasis and influence pulmonary function.Objectives: To identify novel SOD3 polymorphisms that are associated with lung function or chronic obstructive pulmonary disease (COPD).Methods: Resequencing of 182 individuals identified two novel polymorphisms, E1 (rs8192287) and I1 (rs8192288), in a conserved region of the SOD3 gene of potential relationship to lung function. We next genotyped 9,093 individuals from the Copenhagen City Heart Study for the polymorphisms and recorded spirometry, and admissions and deaths due to COPD during 26-year follow-up. Finally, we validated our findings in a cross-sectional analysis of 35,635 individuals from the Copenhagen General Population Study.Measurements and Main Results: Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarriers (Hardy-Weinberg equilibrium: P = 0.93). Using quadruple lung function measurements, we found that E1/I1 homozygotes had 7% lower FVC % predicted (P = 0.006) and 4% lower FEV(1) % predicted (P = 0.12) compared with noncarriers. In the Copenhagen General Population Study, E1/I1 homozygotes also had lower FVC % predicted than noncarriers (P = 0.03), confirming an association between E1/I1 genotype and reduced lung function. E1/I1 homozygotes had adjusted hazard ratios for COPD hospitalization and COPD mortality of 2.5 (95% confidence interval, 1.0-5.9) and 3.7 (95% confidence interval, 0.9-15), respectively; the results were independent of influence from the R213G allele of the SOD3 gene.Conclusions: We identified two novel polymorphisms in a conserved region of the SOD3 gene and show that individuals that are homozygous for these polymorphisms have reduced FVC % predicted in two large, population-based studies. [ABSTRACT FROM AUTHOR]

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown., Objective: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history., Methods: We analyzed data from COPDGene participants with ≥10 pack-years cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator forced expiratory volume in 1 second (FEV 1 )/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FEV 1 ≥LLN. We examined whether respiratory exacerbations occurring between Visits 1 and the 5-year follow-up visit (Visit 2) were associated with FEV 1 decline, and all-cause mortality., Measurements and Main Results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between visit 1 and 2 was associated with a 2.96 ml/year FEV 1 decline (95%CI 1.81 to 4.12; P<0.001) at Visit 2. Experiencing ≥1 severe exacerbation between Visits 1 and 2 was associated with 14.6 ml/year FEV 1 decline relative to those with no severe exacerbations (95% CI 8.56 to 20.6; P<0.001). Individuals with ≥1 severe exacerbation between Visits 1 and 2 had increased mortality compared to those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio 1.97;95% CI 1.40 to 2.77; P<0.001)., Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.

Abstract: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study ( n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [ CDKN2B-AS1 ] among all COPDGene participants ( p = 7.1 × 10 -14 ) and among males ( p = 1.0 × 10 -9 ), but the signal was not genome-wide significant among females ( p = 6.4 × 10 -6 ). For the sex stratified GWA analyses among females, the chromosome 6p24 region [ PHACTR1 ] had a genome-wide significant association ( p = 4.4 × 10 -8 ) with CAC, but this signal was not genome-wide significant among all COPDGene participants ( p = 1.7 × 10 -7 ) or males ( p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex ( p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex ( p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers ( p = 6.2 × 10 -7 ) than former smokers ( p = 7.5 × 10 -3 ) and the SNP by smoking status interaction was marginally significant ( p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former ( p = 7.7 × 10 -8 ) and current smokers ( p = 1.7 × 10 -7 ) and the SNP by smoking status interaction was not significant ( p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [ PHACTR1 ] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White ( n  = 6,766) and AA ( n  = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Background CT attenuation is affected by lung volume, dosage, and scanner bias, leading to inaccurate emphysema progression measurements in multicenter studies. Purpose To develop and validate a method that simultaneously corrects volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT in a longitudinal multicenter study. Materials and Methods In this secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, lung function data were obtained from participants who completed baseline and 5-year follow-up visits from January 2008 to August 2017. CT emphysema progression was measured with volume-adjusted lung density (VALD) and compared with the joint volume-noise-bias-adjusted lung density (VNB-ALD). Reproducibility was studied under change of dosage protocol and scanner model with repeated acquisitions. Emphysema progression was visually scored in 102 randomly selected participants. A stratified analysis of clinical characteristics was performed that considered groups based on their combined lung density change measured by VALD and VNB-ALD. Results A total of 4954 COPDGene participants (mean age, 60 years ± 9 [SD]; 2511 male, 2443 female) were analyzed (1329 with repeated reduced-dose acquisition in the follow-up visit). Mean repeatability coefficients were 30 g/L ± 0.46 for VALD and 14 g/L ± 0.34 for VNB-ALD. VALD measurements showed no evidence of differences between nonprogressors and progressors (mean, -5.5 g/L ± 9.5 vs -8.6 g/L ± 9.6; P = .11), while VNB-ALD agreed with visual readings and showed a difference (mean, -0.67 g/L ± 4.8 vs -4.2 g/L ± 5.5; P < .001). Analysis of progression showed that VNB-ALD progressors had a greater decline in forced expiratory volume in 1 second (-42 mL per year vs -32 mL per year; Tukey-adjusted P = .002). Conclusion Simultaneously correcting volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT improved repeatability analyses and agreed with visual readings. It distinguished between progressors and nonprogressors and was associated with a greater decline in lung function metrics. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( ARSE and MMP16 ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease., Competing Interests: Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Leslie S. Emery is now an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, or interpretation of this study. Nathan O. Stitziel has received research funding from Regeneron Pharmaceuticals, unrelated to this work. Karine A. Viaud-Martinez is an employee at Illumina Inc. Ryan W. Kim is an employee at Psomagen Inc. Roxona Mehran reports institutional research grants from Abbott Laboratories, Abiomed, Applied Therapeutics, AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich; consultant fees from Abbott Laboratories, Boston Scientific, CardiaWave, Chiesi, Janssen Scientific Affairs, Medscape/WebMD, Medtelligence (Janssen Scientific Affairs), Roivant Sciences, Sanofi, Siemens Medical Solutions; consultant fees paid to the institution from Abbott Laboratories, Bristol-Myers Squibb; advisory board, funding paid to the institution from Spectranetics/Philips/Volcano Corp; consultant (spouse) from Abiomed, The Medicines Company, Merck; Equity <1% from Claret Medical, Elixir Medical; DSMB Membership fees paid to the institution from Watermark Research Partners; consulting (no fee) from Idorsia Pharmaceuticals Ltd., Regeneron Pharmaceuticals; Associate Editor for ACC, AMA. Rajeev Malhotra is a consultant for MyoKardia (now owned by BMS), Epizon Pharma, Renovacor, and Third Pole, a co-founder of Patch and Angea Biotherapeutics, and has received research funding from Angea Biotherapeutics, Bayer Pharmaceuticals, and Amgen. Adrienne M. Stilp receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. Pradeep Natarajan reports grants from Amgen, Apple, Boston Scientific, AstraZeneca, Allelica, Novartis, and Genentech, consulting income from GV, Blackstone Life Sciences, Foresite Labs, Apple, AstraZeneca, Allelica, Novartis, HeartFlow, and Genentech, is a scientific advisor to Esperion Therapeutics, Preciseli, and TenSixteen Bio, is a scientific co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. Clint L. Miller received a research grant from AstraZeneca for an unrelated project. The remaining authors declare no competing interests.

Background: FOOTPRINTS ® is a prospective, longitudinal, 3-year study assessing the association between biomarkers of inflammation/lung tissue destruction and chronic obstructive pulmonary disease (COPD) severity and progression in ex-smokers with mild-to-severe COPD. Here, we present baseline characteristics and select biomarkers of study subjects., Methods: The methodology of FOOTPRINTS ® has been published previously. The study population included ex-smokers with a range of COPD severities (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-3), ex-smokers with COPD and alpha-1-antitrypsin deficiency (A1ATD) and a control group of ex-smokers without airflow limitation (EwAL). At study entry, data were collected for: demographics, disease characteristics, history of comorbidities and COPD exacerbations, symptoms, lung function and volume, exercise capacity, soluble biomarkers, and quantitative and qualitative computed tomography. Baseline data are presented with descriptive statistical comparisons for soluble biomarkers in the individual GOLD and A1ATD groups versus EwAL., Results: In total, 463 subjects were enrolled. The per-protocol set comprised 456 subjects, mostly male (64.5%). The mean (standard deviation) age was 60.7 (6.9) years. At baseline, increasing pulmonary symptoms, worse lung function, increased residual volume, reduced diffusing capacity of the lung for carbon monoxide (DLco) and greater prevalence of centrilobular emphysema were observed with increasing disease severity amongst GOLD 1-3 subjects. Subjects with A1ATD (n = 19) had similar lung function parameters to GOLD 2-3 subjects, a high residual volume comparable to GOLD 3 subjects, and similar air trapping to GOLD 2 subjects. Compared with EwAL (n = 61), subjects with A1ATD had worse lung function, increased residual volume, reduced DLco, and a greater prevalence of confluent or advanced destructive emphysema. The soluble inflammatory biomarkers white blood cell count, fibrinogen, high-sensitivity C-reactive protein and plasma surfactant protein were higher in GOLD 1-3 groups than in the EwAL group. Interleukin-6 was expressed less often in EwAL subjects compared with subjects in the GOLD and A1ATD groups. Soluble receptor for advanced glycation end product was lowest in GOLD 3 subjects, indicative of more severe emphysema., Conclusions: These findings provide context for upcoming results from FOOTPRINTS ® , which aims to establish correlations between biomarkers and disease progression in a representative COPD population., Trial Registration Number: NCT02719184, study start date 13/04/2016., (© 2023. The Author(s).)

The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed and obtained IRB approval for a process of returning HCV research results and an HCV Follow-Up Study questionnaire to capture information about previous HCV diagnosis and treatment information and participant reactions to return of HCV results. During phone calls following the initial HCV notification letter, 84 of 124 participants who could be contacted (67.7%) volunteered that they had been previously diagnosed with HCV infection. Thirty-one of these 124 COPDGene participants were enrolled in the HCV Follow-Up Study. Five of the 31 HCV Follow-Up Study participants did not report a previous diagnosis of HCV. For four of these participants, subsequent clinical HCV testing confirmed HCV infection. Thus, 30/31 Follow-Up Study participants had confirmed HCV diagnoses, supporting the accuracy of the HCV research test results. However, the limited number of participants in the Follow-Up Study precludes an accurate assessment of the false-positive and false-negative rates of the research RNA sequencing evidence for HCV. Most HCV Follow-Up Study participants (29/31) were supportive of returning HCV research results, and most participants found the process for returning HCV results to be informative and not upsetting. Newly diagnosed participants were more likely to be pleased to learn about a potentially curable infection (p = 0.027) and showed a trend toward being more frightened by the potential health risks of HCV (p = 0.11). We conclude that HCV results identified incidentally during transcriptomic research studies can be successfully returned to research study participants with a carefully designed process., (© 2023. The Author(s).)