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Asthma and COPD are common respiratory diseases that are caused by the interaction of genetic susceptibility with environmental factors. Environmental influences are important in both diseases, and although there are differences in genetic susceptibilities, there are also similarities. Three examples of interest for both asthma and COPD patients are discussed. The first is the results of family studies, which have shown evidence for susceptibility loci for both asthma-related and COPD-related phenotypes in the same chromosomal region. Second, evidence for a gene-environment interaction with passive smoking for asthma patients compared with individual smoking for COPD patients will be covered. The third is an example of one candidate gene (interleukin-13), in which similar results have been observed for both asthma and COPD. [ABSTRACT FROM AUTHOR]

Allergic diseases are most likely due to interactions between genetic and environmental factors. While many of the environmental components have been studied for years, only recently has significant progress been made in identifying the genes responsible for susceptibility or expression of these diseases. Genome-wide screens in various populations have identified the locations of susceptibility genes for asthma and atopy, as well as associated phenotypes such as bronchial hyperresponsiveness and increased total serum IgE levels. In addition, this positional cloning approach has led to the discovery of several genes for asthma or related phenotypes, which is extending our understanding of the pathophysiology of allergic diseases. As these genes are identified and characterized, the relationships of these genes to each other and the environment will become important areas of research. Understanding the basic interactions that lead to the development of allergy and asthma will lead to new therapeutic approaches that will be used to modify the development and clinical progression of these common disorders. [ABSTRACT FROM AUTHOR]

Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people., Competing Interests: Declaration of interests The authors declare no competing interests. D.P.L. is now an employee of AstraZeneca. This is unrelated to the work of this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions., Objectives: Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach., Methods: In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to analyze 11 clinical characteristics simultaneously. The annualized asthma exacerbation rate, exacerbation incidence, and lung function were analyzed across clusters., Results: Patients (n = 2,281) met criteria for four of five clusters: cluster 2 (early-onset moderate asthma, n = 393), cluster 4 (early-onset severe asthma, n = 386), cluster 3 (late-onset severe asthma, n = 641), and cluster 5 (late-onset severe, obstructed asthma, n = 861); no patients met cluster 1 criteria. Exacerbation rate reductions were significant in late-onset severe asthma (-48% [95% CI, -61% to -31%]; P < .0001) and late-onset severe, obstructed asthma (-50% [95% CI, -59% to -38%]; P < .0001), with nonsignificant reductions in early-onset clusters. These differences could not be fully explained by blood eosinophil count differences. Values for improvements in FEV 1 were significant in late-onset severe asthma (+133 mL [95% CI, 66-200]; P = .0001) and late-onset severe, obstructed asthma (+160 mL [95% CI, 85-235]; P < .0001) while maintaining acute bronchodilator responsiveness., Conclusions: Benralizumab reduced exacerbations and improved lung function, primarily in late-onset asthma clusters. This multivariate approach to identify subphenotypes, potentially reflecting pathobiological mechanisms, can guide therapy beyond univariate approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition., Objectives: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression., Methods/discussion: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture., Conclusion: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis., (JCOPDF © 2024.)

Background: Asthma pathophysiology is associated with mitochondrial dysfunction. Mitochondrial DNA copy number (mtDNA-CN) has been used as a proxy of mitochondrial function, with lower levels indicating mitochondrial dysfunction in population studies of cardiovascular diseases and cancers., Objectives: We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations., Methods: mtDNA-CN is evaluated in blood from 2 cohorts: UK Biobank (UKB) (asthma, n = 39,147; no asthma, n = 302,302) and Severe Asthma Research Program (SARP) (asthma, n = 1283; nonsevere asthma, n = 703)., Results: Individuals with asthma have lower mtDNA-CN compared to individuals without asthma in UKB (beta, -0.006 [95% confidence interval, -0.008 to -0.003], P = 6.23 × 10 -6 ). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in individuals with asthma than in individuals without asthma at all ages. In a 1-year longitudinal study in SARP, mtDNA-CN was associated with risk of exacerbation; those with highest mtDNA-CN had the lowest risk of exacerbation (odds ratio 0.333 [95% confidence interval, 0.173 to 0.542], P = .001). Biomarkers of inflammation and oxidative stress are higher in individuals with asthma than without asthma, but the lower mtDNA-CN in asthma is independent of general inflammation or oxidative stress. Mendelian randomization studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN., Conclusion: mtDNA-CN is lower in asthma than in no asthma and is associated with exacerbations. Low mtDNA-CN in asthma is not mediated through inflammation but is associated with a genetic predisposition to asthma., Competing Interests: Disclosure statement This research was conducted using the UK Biobank Resource under application 17731. The study was supported by the National Heart, Lung, and Blood Institute (NHLBI; HL081064, HL103453, and HL144569) and the National Center for Advancing Translational Sciences (ULTR000439). The Severe Asthma Research Program (SARP) was supported by awards from the National Heart, Lung, and Blood Institute (U10 HL109172, U10 HL109168, U10 HL109152, U10 HL109257, U10 HL109046, U10 HL109250, U10 HL109164, and U10 HL109086). SARP mitochondrial DNA copy numbers were from the Trans-omics in Precision Medicine (TOPMed) program supported by the NHLBI. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general program coordination was provided by the TOPMed Data Coordinating Center (R01HL120393; U01HL120393; contract HHSN268201800001I). Industry support was provided for SARP III from AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and Teva. The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and Teva. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Circulating metabolite levels partly reflect the state of human health and diseases, and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally-diverse samples. We provided recommendations for outlier and imputation handling to process metabolite data, as well as a general analytical framework. We further performed a pooled analysis following our practical recommendations and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus - metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes, but also novel genes (such as GAB3 and VSIG4 located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such as FADS2 , D2HGDH , SUGP1 , UTG2B17 , strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

Background: Asthma classification into different subphenotypes is important to guide personalized therapy and improve outcomes., Objectives: To further explore asthma heterogeneity through determination of multiple patient groups by using novel machine learning (ML) approaches and large-scale real-world data., Methods: We used electronic health records of patients with asthma followed at the Cleveland Clinic between 2010 and 2021. We used k-prototype unsupervised ML to develop a clustering model where predictors were age, sex, race, body mass index, prebronchodilator and postbronchodilator spirometry measurements, and the usage of inhaled/systemic steroids. We applied elbow and silhouette plots to select the optimal number of clusters. These clusters were then evaluated through LightGBM's supervised ML approach on their cross-validated F1 score to support their distinctiveness., Results: Data from 13,498 patients with asthma with available postbronchodilator spirometry measurements were extracted to identify 5 stable clusters. Cluster 1 included a young nonsevere asthma population with normal lung function and higher frequency of acute exacerbation (0.8 /patient-year). Cluster 2 had the highest body mass index (mean ± SD, 44.44 ± 7.83 kg/m 2 ), and the highest proportion of females (77.5%) and Blacks (28.9%). Cluster 3 comprised patients with normal lung function. Cluster 4 included patients with lower percent of predicted FEV 1 of 77.03 (12.79) and poor response to bronchodilators. Cluster 5 had the lowest percent of predicted FEV 1 of 68.08 (15.02), the highest postbronchodilator reversibility, and the highest proportion of severe asthma (44.9%) and blood eosinophilia (>300 cells/μL) (34.8%)., Conclusions: Using real-world data and unsupervised ML, we classified asthma into 5 clinically important subphenotypes where group-specific asthma treatment and management strategies can be designed and deployed., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP , DSP , and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation., (© 2024. The Author(s).)

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC + mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma., (© 2024. The Author(s).)

Introduction: Previous bronchoalveolar lavage fluid (BALF) proteomic analysis has evaluated limited numbers of subjects for only a few proteins of interest, which may differ between asthma and normal controls. Our objective was to examine a more comprehensive inflammatory biomarker panel in quantitative proteomic analysis for a large asthma cohort to identify molecular phenotypes distinguishing severe from nonsevere asthma., Methods: Bronchoalveolar lavage fluid from 48 severe and 77 nonsevere adult asthma subjects were assessed for 75 inflammatory proteins, normalized to BALF total protein concentration. Validation of BALF differences was sought through equivalent protein analysis of autologous sputum. Subjects' data, stratified by asthma severity, were analysed by standard statistical tests, principal component analysis and 5 machine learning algorithms., Results: The severe group had lower lung function and greater health care utilization. Significantly increased BALF proteins for severe asthma compared to nonsevere asthma were fibroblast growth factor 2 (FGF2), TGFα, IL1Ra, IL2, IL4, CCL8, CCL13 and CXCL7 and significantly decreased were platelet-derived growth factor a-a dimer (PDGFaa), vascular endothelial growth factor (VEGF), interleukin 5 (IL5), CCL17, CCL22, CXCL9 and CXCL10. Four protein differences were replicated in sputum. FGF2, PDGFaa and CXCL7 were independently identified by 5 machine learning algorithms as the most important variables for discriminating severe and nonsevere asthma. Increased and decreased proteins identified for the severe cluster showed significant protein-protein interactions for chemokine and cytokine signalling, growth factor activity, and eosinophil and neutrophil chemotaxis differing between subjects with severe and nonsevere asthma., Conclusion: These inflammatory protein results confirm altered airway remodelling and cytokine/chemokine activity recruiting leukocytes into the airways of severe compared to nonsevere asthma as important processes even in stable status., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT)., Objective: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT., Methods: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort., Results: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p = 0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p = 0.006) for subjects with a higher number of elevated T2 biomarkers., Conclusions: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype., Trial Registration Number: NCT01433523., Competing Interests: Competing interests: IH is an employee of ALK-Abelló A/S. KB has acted as a paid consultant for ALK-Abelló A/S, AstraZeneca, Boehringer Ingelheim and Sanofi. TS is an employee of ALK-Abelló A/S. SB was an employee of ALK-Abelló A/S when data analysis took place. MHS receives grant support via Imperial College London from the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases, Medical Research council, ALK-Abelló A/S, Regeneron, and serves as a consultant for Allergy Therapeutics, Angany, and UCB. EDB is a member of the Science Committee and Board of GINA. He reports personal fees from ALK-Abelló A/S in relation to the current submission, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Novartis, Orion, Regeneron and Sanofi Genzyme, outside the submitted work. EB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme, and has served as a paid consultant for ALK-Abelló A/S, AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, Regeneron, Sanofi Genzyme and TEVA, outside the submitted work. PSA is an employee of ALK-Abelló A/S., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P  = 7.1 × 10 -95 ) and PRS-NO-M5B (OR per SD, 2.8; P  = 2.5 × 10 -87 ) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Objective: Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP)., Methods: Correlation analyses of mRNA expression of six candidate genes ( AP2A2 , MUC6 , MUC2 , MUC5AC , MUC5B , and TOLLIP ) and asthma phenotypes were performed in the longitudinal cohort ( n  = 156) with RNAseq in BEC, and replicated in the cross-sectional cohort ( n  = 155). eQTL ( n  = 114) and genetic association analysis of asthma severity (426 severe vs. 531 non-severe asthma) were performed, and compared with previously published GWASs of IIPs and asthma., Results: Higher expression of AP2A2 and MUC5AC and lower expression of MUC5B in BEC were correlated with asthma, asthma exacerbations, and T2 biomarkers ( P  < 0.01). SNPs associated with asthma and IIPs in previous GWASs were eQTL SNPs for MUC5AC , MUC5B , or TOLLIP , however, they were not in strong linkage disequilibrium. The risk alleles for asthma or protective alleles for IIPs were associated with higher expression of MUC5AC and lower expression of MUC5B . rs11603634, rs12788104, and rs28415845 associated with moderate-to-severe asthma or adult onset asthma in previous GWASs were not associated with asthma severity ( P  > 0.8)., Conclusions: SNPs associated with asthma in chr11p15.5 region are not associated with asthma severity neither with IIPs. Higher expression of MUC5AC and lower expression of MUC5B are risk for asthma but protective for IIPs.

Objective: Subphenotypes of asthma may be determined by age onset and atopic status. We sought to characterize early or late onset atopic asthma with fungal or non-fungal sensitization (AAFS or AANFS) and non-atopic asthma (NAA) in children and adults in the Severe Asthma Research Program (SARP). SARP is an ongoing project involving well-phenotyped patients with mild to severe asthma., Methods: Phenotypic comparisons were performed using Kruskal-Wallis or chi-square test. Genetic association analyses were performed using logistic or linear regression., Results: Airway hyper-responsiveness, total serum IgE levels, and T2 biomarkers showed an increasing trend from NAA to AANFS and then to AAFS. Children and adults with early onset asthma had greater % of AAFS than adults with late onset asthma (46% and 40% vs. 32%; P  < 0.00001). In children, AAFS and AANFS had lower % predicted FEV 1 (86% and 91% vs. 97%) and greater % of patients with severe asthma than NAA (61% and 59% vs. 43%). In adults with early or late onset asthma, NAA had greater % of patients with severe asthma than AANFS and AAFS (61% vs. 40% and 37% or 56% vs. 44% and 49%). The G allele of rs2872507 in GSDMB had higher frequency in AAFS than AANFS and NAA (0.63 vs. 0.55 and 0.55), and associated with earlier age onset and asthma severity., Conclusions: Early or late onset AAFS, AANFS, and NAA have shared and distinct phenotypic characteristics in children and adults. AAFS is a complex disorder involving genetic susceptibility and environmental factors.

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants., Competing Interests: Conflicts of interest statement TL is a paid advisor to GSK, Pfizer, Goldfinch Bio, and Variant Bio and has equity in Variant Bio., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals., Objectives: To characterize the impact of bronchiectasis on COPD and explore alpha-1antitrypsin as a risk factor for bronchiectasis., Methods: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) participants (N=914; ages 40-80 years; ≥20-pack-year smoking) had high-resolution computed tomography (CT) scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding -alpha-1 antitrypsin, SERPINA1 , in 835 participants to test for rare variants, focusing on the PiZ genotype (Glu 366 Lys, rs28929474)., Measurements and Main Results: We identified bronchiectasis in 365 (40%) participants, more frequently in women (45% versus 36%, p =0.0045), older participants (mean age=66[standard deviation (SD)=8.3] versus 64[SD=9.1] years, p =0.0083), and those with lower lung function (forced expiratory volume in 1 second [FEV 1 ] percentage predicted=66%[SD=27] versus 77%[SD=25], p <0.0001; FEV 1 to forced vital capacity [FVC] ratio=0.54[0.17] versus 0.63[SD=0.16], p <0.0001). Participants with bronchiectasis had greater emphysema (%voxels ≤-950 Hounsfield units, 11%[SD=12] versus 6.3%[SD=9], p <0.0001) and parametric response mapping functional small airways disease (26[SD=15] versus 19[SD=15], p <0.0001). Bronchiectasis was more frequent in the combined PiZZ and PiMZ genotype groups compared to those without PiZ, PiS, or other rare pathogenic variants (N=21 of 40 [52%] versus N=283 of 707[40%], odds ratio [OR]=1.97; 95% confidence interval [CI]=1.002, 3.90, p =0.049), an association attributed to White individuals (OR=1.98; 95%CI = 0.9956, 3.9; p =0.051)., Conclusions: Bronchiectasis was common in those with heavy smoking histories and was associated with detrimental clinical and radiographic outcomes. Our findings support alpha-1antitrypsin guideline recommendations to screen for alpha-1 antitrypsin deficiency in an appropriate bronchiectasis subgroup with a significant smoking history., (JCOPDF © 2023.)

Background: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear., Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation., Methods: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1 high murine severe asthma model., Results: Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5 high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1 high /T2 variable /lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation., Conclusion: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to link SomaScan 1.3K proteomes to genomes for 2812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We correctly linked 90-95% of proteomes to their correct genome and for 95-99% we identify the 1% most likely links. The linking accuracy in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. We also linked proteomes-to-proteomes and used the proteome only to determine features such as sex, ancestry, and first-degree relatives. When serial proteomes are available, the linking algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable., (© 2023. The Author(s).)

Background: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication., Objective: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs., Methods: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression., Results: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs., Conclusions: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The stability and variability of blood eosinophil counts (BECs) to phenotype patients with severe asthma is not fully understood., Objective: This post hoc, longitudinal, pooled analysis of placebo-arm patients from 2 phase 3 studies evaluated the clinical implications of BEC stability and variability in moderate-to-severe asthma., Methods: This analysis included patients from SIROCCO and CALIMA who received maintenance medium- to high-dosage inhaled corticosteroids plus long-acting β 2 -agonists; 2:1 patients with BECs of 300 cells/μL or higher and less than 300 cells/μL were enrolled. The BECs were measured 6 times over 1 year in a centralized laboratory. Exacerbations, lung function, and Asthma Control Questionnaire 6 scores were documented across patients grouped by BEC (<300 cells/μL or ≥300 cells/μL) and variability (<80% or ≥80% BECs less than or greater than 300 cells/μL)., Results: Among 718 patients, 42.2% (n = 303) had predominantly high, 30.9% (n = 222) had predominantly low, and 26.9% (n = 193) had variable BECs. Prospective exacerbation rates (mean ± SD) were significantly greater in patients with predominantly high (1.39 ± 2.20) and variable (1.41 ± 2.09) BECs versus predominantly low (1.05 ± 1.66) BECs. Similar results were observed for the number of exacerbations while on placebo., Conclusions: Although patients with variable BECs had intermittently high and low BECs, they experienced similar exacerbation rates to the predominantly high group, which were greater than those in the predominantly low group. A high BEC supports an eosinophilic phenotype in clinical settings without additional measurements, whereas a low BEC requires repeated measurements because it could reflect intermittently high or predominantly low BECs., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV 1 ) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV 1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD., (© 2023. The Author(s).)

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies., (© 2023. The Author(s).)

Rationale: CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Methods: Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Measurements and Main Results: Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes ( IL1RL1 , POSTN , SERPINB2 , CLCA1 , NOS2 , and MUC5AC ) and positively correlated with expression levels of Th1 and inflammation genes ( IL12A and MUC5B ). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Conclusions: Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1-4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction., (© 2022. The Author(s).)

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV 1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV 1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV 1 responses to β-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV 1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P  < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown., Objective: We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype., Methods: We transfected HASM with a range of RGS2-specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3., Results: RGS2-specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P < .0001) with a concomitant decrease in RGS2 protein expression. RGS2-specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P = .42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r 2  = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (P additive  = 2.86 × 10 -5 /P recessive  = 5.22 × 10 -6 and P additive  = 3.46 × 10 -6 /P recessive  = 6.74 × 10 -7 , respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data., Conclusion: RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4; P < .001). Lower whole-lung Jacobian and ADI values were associated with greater cluster severity. Compared to cluster 1, cluster 5 lung expansion was 31% smaller (Jacobian in SARP III cohort: 2.31 ± 0.6 vs 1.61 ± 0.3, respectively, P < .001) and 34% more isotropic (ADI in SARP III cohort: 0.40 ± 0.1 vs 0.61 ± 0.2, P < .001). Within-lung Jacobian and ADI SDs decreased as severity worsened (Jacobian SD in SARP III cohort: 0.90 ± 0.4 for cluster 1; 0.79 ± 0.3 for cluster 2; 0.62 ± 0.2 for cluster 3; 0.63 ± 0.2 for cluster 4; and 0.41 ± 0.2 for cluster 5; P < .001). Conclusion Quantitative CT assessments of the degree and intraindividual regional variability of lung expansion distinguished between well-established clinical phenotypes among participants with asthma from the Severe Asthma Research Program study. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Introduction: Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology., Methods: We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts., Results: A total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p<5×10 -8 ). Performing fine mapping and using a threshold of p<5×10 -6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1 ), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284 ), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2 ), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age-genotype interaction effects., Conclusion: Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR., Competing Interests: Conflict of interest: J.D. Gereige reports that support for the present manuscript received from NIH; grants or contracts from NIH, outside the submitted work; and support for attending meetings received from ACAAI, outside the submitted work. Conflict of interest: H. Xu reports that support for the present manuscript received from NIH. Conflict of interest: V.E. Ortega reports that support for the present manuscript received from NHLBI; AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici SpA; Forest Research Institute, Inc.; GSK; Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc; and Sanofi. Consulting fees received from Sanofi and Regeneron, outside the submitted work. Conflict of interest: M.H. Cho reports that support for the present manuscript has been received from NHLBI; grants or contracts received from Bayer and GSK, outside the submitted work; consulting fees received from AstraZeneca and Genentech, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Illumina, outside the submitted work. Conflict of interest: E.K. Silverman reports that support for the present manuscript received from NIH; and grants or contracts received from Bayer and GlaxoSmithKline, outside the submitted work. Conflict of interest: C.P. Hersh reports that support for the present manuscript has been received from National Institutes of Health; grants or contracts received from Bayer, Boehringer-Ingelheim, Novartis, Vertex and Alpha-1 Foundation, outside the submitted work; and consulting fees received from Takeda, outside the submitted work. Conflict of interest: J.D. Morrow reports that support for the present manuscript received from NIH NHLBI. Conflict of interest: B.E. Miller is a shareholder at GSK; disclosure made outside the submitted work. Conflict of interest: P. Bakke reports receiving payment for lectures from GlaxoSmithKline, Boehringer-Ingelheim, Novartis and AstraZeneca, outside the submitted work; and an advisory Board fee received from AstraZeneca, outside the submitted work. Conflict of interest: E.R. Bleecker reports receiving grants or contracts from AstraZeneca, Novartis, Regeneron and Sanofi Genzyme, outside the submitted work; consulting fees received from ALK-Abello, AstraZeneca, Glaxo Smith Kline, Knopp Pharmaceuticals, Novartis, Regeneron and Sanofi Genzyme, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from ALK-Abello, AstraZeneca and GlaxoSmithKline, outside the submitted work; and support for attending meetings and/or travel received from ALK-Abello, AstraZeneca, GlaxoSmithKline, Novartis, Regeneron and Sanofi Genzyme, outside the submitted work. The following companies provided financial support for the NHLBI SARP study activities at the Coordinating and Clinical Centers: AstraZeneca, Boehringer-Ingelheim, Genentech, Sanofi-Genzyme-Regeneron, and TEVA; these companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative. Conflict of interest: S.P Peters reports that support for the present manuscript received from NHLBI; AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici SpA; Forest Research Institute, Inc.; GSK; Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; and Sanofi. Consulting fees received from NIAID, GSK, Syneos, and Parexel, outside the submitted work. Conflict of interest: K. Tantisira reports grants or contracts received from National Institutes of Health, outside the submitted work. Conflict of interest: J. Li reports that support for the present manuscript received from NIH. Conflict of interest: J. Dupuis reports that support for the present manuscript received from NIH/NHLBI Framingham Heart Study contract. Conflict of interest: G.T. O'Connor reports that support for the present manuscript received from NIH and grants or contracts received from NIH outside the submitted work., (Copyright ©The authors 2022.)

Introduction: Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies., Methods: We applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6-8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables., Results: PC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV 1 change (Kendall tau-b R=-0.333 (-0.592 to -0.012)) and follow-up FEV 1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV 1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset., Conclusions: Transcriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone., Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?, Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10 -6 ) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2)., Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10 -8 ) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent., Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10 -9 ) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 ( STN1 ). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B ( SNM1B ) and PARN . In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes., Competing Interests: Declaration of Interests: The authors declare the following competing interests: J.C.C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. B.I.F. is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI L.W. is on the advisory board for GlaxoSmithKline and receives grant funding from NIAID, NHLBI, and NIDDK, NIH I.V.Y. is a consultant for ElevenP15 S.A. receives equity and salary from 23andMe, Inc. M.H.C. receives grant support from GlaxoSmithKline S.T.W. receives royalties from UpToDate E.K.S. received grant support from GlaxoSmithKline and Bayer in the past three years. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. F.D.M. is supported by grants from NIH/NHLBI (HL139054,HL091889,HL132523,HL130045,HL098112,HL056177), the NIH/NIEHS (ES006614), the NIH/NIAID (AI126614), and the NIH/ Office of Director (OD023282). Vifor Pharmaceuticals provided medicine and additional funding to support recruitment for HL130045. Dr. Martinez is a council member for the Council for the Developing Child. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Dr. Ellinor has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. K.C.B. receives royalties from UpToDate G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.M. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.B. is a consultant for Third Rock Ventures, LLC and holds stock in Google, Inc. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis

Background: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent., Methods: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV 1 . We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10 -4 , and tested for replication using independent cohorts of individuals of African descent with asthma., Findings: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [OR local African ] 3·95, 95% CI 2·02-7·72, p=6·1 × 10 -5 ) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, OR allele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10 -5 ). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (OR local African 3·35, 1·98-5·67, p=6·8 × 10 -6 ) containing a locus adjacent to TPST2 (rs5752429, OR allele dose 0·21, 0·09-0·52, p=5·7 × 10 -4 ). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts., Interpretation: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma., Funding: National Institutes of Health, National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests VEO reports consulting fees from Sanofi and fees for serving on independent data monitoring committees for Sanofi and Regeneron Pharmaceuticals. SJS reports receiving consulting fees, paid to his institution, from AstraZeneca, GlaxoSmithKline, Moderna, Propeller Health, Regeneron, and Sanofi, as well as a research grant from Propeller Health. ERB reports receiving consulting fees and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, consulting fees from AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, and Sanofi–Regeneron, and participating in trials as an employee of Wake Forest School of Medicine and the University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Cephalon–Teva Pharmaceuticals, Genentech, GlaxoSmithKline, Johnson & Johnson (Janssen), Novartis, and Sanofi–Regeneron. VMC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. WP reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DM reports receiving grant support and donated drugs from GlaxoSmithKline, Genentech, Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, fees for serving on a data and safety monitoring board from Novartis, and donated drugs from Merck. FDM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support from Johnson & Johnson, and consulting fees from Copeval and Commence. EH-L reports a fellowship from the Spanish Ministry of Science, Innovation, and Universities. MP-Y reports grants from the Spanish Ministry of Economy, Industry, and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MICIU/AEI/FEDER, UE), and grant support from GlaxoSmithKline, Spain. SJK reports receiving donated drugs from Merck–Organon, Genentech, GlaxoSmithKline, and Regeneron and owning stock in Merck. LBB reports receiving consulting fees and lecture fees from Aerocrine, GlaxoSmithKline, Genentech–Novartis, and AstraZeneca, advisory board fees and donated drugs from Merck, fees for serving on a data safety monitoring board from DBV Technologies, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals and Boehringer Ingelheim, honoraria from WebMD–Medscape, advisory board fees and lecture fees from Sanofi–Regeneron, advisory board fees and consulting fees from Vectura, and advisory board fees from Circassia. MDC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and consulting fees from Genentech and Novartis. JCC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. MC reports receiving grant support, lecture fees, and donated drugs from Boehringer Ingelheim, donated drugs from Merck, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals, consulting fees and lecture fees from Boston Scientific and Genentech, consulting fees from Nuvaira, Aviragen, 4D Pharma, VIDA Diagnostics, Mallinckrodt Pharmaceuticals, Theravance, Therabron, and Vectura, grant support, consulting fees, and lecture fees from Sanofi-Aventis, grant support and lecture fees from AstraZeneca and GlaxoSmithKline, grant support from Chiesi and Novartis, and lecture fees from Regeneron Pharmaceuticals. LCD reports receiving grant support and consulting fees from AstraZeneca, and consulting fees from Sanofi–Regeneron. FH reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DJJ reports grant support from GlaxoSmithKline, consulting fees from Novartis, Sanofi, Regeneron, Vifor Pharma, and AstraZeneca, and fees for serving on a data and safety monitoring board from Pfizer. NJ reports receiving honorarium for consulting from GlaxoSmithKline pharmaceuticals and Pulmocide. MK reports receiving grant support from Chiesi and Sanofi. JAK reports personal fees for independent data monitoring committee participation from Sanofi and research funding from the American Lung Association—Airway Clinical Research Centers Network. SCL reports grant funding from the American Lung Association—Airway Clinical Research Centers Network. RFL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and lecture fees from Thermo Fisher Scientific. JJL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. NL reports receiving grant support, advisory board fees, and donated drugs from GlaxoSmithKline, grant support, consulting fees, and advisory board fees from AstraZeneca, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, grant support from Genentech, grant support and advisory board fees from Sanofi–Regeneron, and donated drugs from Merck and Boehringer Ingelheim. WCM reports receiving grant support and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, grant support and advisory board fees from AstraZeneca, GlaxoSmithKline, and Sanofi–Regeneron, and grant support from Novartis, Cumberland Pharmaceuticals, and Gossamer Bio. SPP reports receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Mylan, Teva Pharmaceuticals, Sanofi–Regeneron, and Theravance, fees for serving as clinical trial adjudicator from Quintiles, fees for serving on a data and safety monitoring board from Genentech, fees for serving as chair of a data and safety monitoring board from Novartis, and honoraria from PRIME. JAP reports receiving donated drugs from Boehringer Ingelheim, Merck, Teva Pharmaceuticals, and GlaxoSmithKline. LJS reports receiving donated drugs from Boehringer Ingelheim and Teva Pharmaceuticals, and fees for serving on a data and safety monitoring board and donated drugs from Merck. JS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, advisory board fees from PulmOne Advanced Medical Devices, advisory board fees, honoraria, and travel support from Regeneron–Sanofi–Genzyme, holding patents #6 090 618, #6 114 311, #6 284 743, #6 291 211, #6 297 221, #6 331 527, and #7 169 764 on a smooth-muscle gene promoter (SM22 alpha), holding pending patent PCT/US2014/032186 on a method for determining respiratory physiological parameters, holding pending patent 62/872,980 on remodilins for airway remodelling and organ fibrosis, and holding pending patent 62/828,122 on remodilins to prevent or treat cancer metastasis, glaucoma, and hypoxia. CAS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. SW reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support and consulting fees from AstraZeneca and Sanofi, and consulting fees from Pieris Pharmaceuticals. DAM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. EI reports receiving grant support and consulting fees from AstraZeneca, Novartis, and Genentech, consulting fees from Regeneron Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi Genzyme, Entrinsic Health Solutions, Pneuma Respiratory, 4D Pharma, Sienna Biopharmaceuticals, and Equillium, grant support, consulting fees, and donated drugs from Merck, Teva Pharmaceutical Industries, and GlaxoSmithKline, serving as a consultant for Vorso, receiving grant support and donated drugs from Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, and donated drugs from Circassia. MEW reports receiving grant support and consulting fees from AstraZeneca, Novartis, Sanofi, and GlaxoSmithKline, consulting fees from Regeneron Pharmaceuticals, Mylan, Genentech, Restorbio, Equillium, Boston Scientific, Genzyme, Gala Therapeutics, and Pulmatrix, fees for serving on a data and safety monitoring board from Sentien Biotechnologies, grant support, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, consulting fees and donated drugs from Boehringer Ingelheim and Merck. MD, GAH, EJA CC, CE, AMF, DH, AM, ETN, SPS, MAS, SRW, EGB, and KB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach., Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m 2 ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data., Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 -8 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling., Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE., Objective: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901)., Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data., Results: We identified 6 loci at genome-wide significance (P < 5 × 10 -9 ), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (P discovery  = 2 × 10 -4 ; P replication  = 5 × 10 -4 ; P discovery+replication  = 4 × 10 -7 ), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (P Hispanic/Latino discovery+replication  = 8 × 10 -8 )., Conclusion: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)