Citations

Summary Asthma genetic architecture varies according to age at onset and biological sex. Medication‐defined severity showed limited common variant genetic heterogeneity compared with age at onset and sex.

Abstract Background Sarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined. Methods We performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV₁% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis. Results Compared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion (∼2.6%) of this association. Conclusions. The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

Abstract Background Chronic Q fever, caused by Coxiella burnetii, presents significant diagnostic and management challenges due to its variable presentation and high morbidity, especially among patients with underlying cardiac or vascular disease. In the United States, cases are rising, often without identifiable exposures, and diagnostic delays remain common. Methods We conducted a retrospective cohort study of chronic Q fever cases at the Mayo Clinic from 2007 to 2023. Patients with clinical evidence and a phase I IgG titer ≥1:1024 and/or positive PCR for C. burnetii were included. Data were abstracted from electronic health records, including demographics, exposures, clinical manifestations, diagnostics, treatments, and outcomes. Statistical analyses assessed factors influencing diagnostic delay and treatment response. Results We identified 33 patients with chronic Q fever (median age 56; 88% male). Median time to diagnosis was 99 days with 11.4 days between Infectious Diseases (ID) evaluation and diagnosis. Animal exposure was reported in 17 patients (52%), while eight (24%) had no identifiable exposure. Patients primarily presented with prosthetic valve endocarditis (n=14, 42%), or vascular graft infection (n=9, 27%). The majority were treated with doxycycline and hydroxychloroquine (n=25, 75%) and 14 patients (42%) required surgical intervention. Mortality attributable to chronic Q fever was 6% (n=2). Conclusions Chronic Q fever remains under-recognized, with substantial diagnostic delays prior to treatment. Cardiovascular infection predominates, and surgical intervention is often required despite prolonged antimicrobial therapy. Early specialist evaluation and standardized diagnostic pathways may improve outcomes.

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

This review identifies the menopausal transition as a critical yet underrecognized determinant of asthma heterogeneity in midlife women. It synthesizes evidence that fluctuating sex hormones may shape distinct asthma phenotypes and endotypes, influencing clinical manifestations, disease modifiers, and therapeutic responses. By framing menopause-associated asthma as a biologically distinct, hormone-driven condition, the article highlights key research priorities for precision medicine approaches tailored to women’s respiratory health.

Abstract Objectives Fibronodular hepatocellular carcinoma (FN-HCC) is a newly described variant of hepatocellular carcinoma (HCC), with only 29 cases reported. Histologically, it is divided into multiple smaller, well-defined tumor nodules by extensive fibrosis. Its differential diagnosis includes other HCC variants characterized by fibrous stroma, such as fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma. Fibronodular hyperplasia may also be considered in the differential diagnosis. We are reporting 7 cases to help better understand this entity. Methods We retrospectively identified 7 cases of FN-HCC and analyzed the clinical and histologic features of each tumor, as well as disease progression and patient prognosis. Results The FN-HCC cases were diagnosed at a median age of 58 years (range, 40-75 years), with a male predilection (n = 6, 86%). Most patients were White (n = 6, 86%), and 1 was African American (n = 1, 14%). Tumors had a mean size of 3.15 cm (range, 1-9 cm) and were mainly located in the right lobe (n = 5, 71%). Background liver was cirrhotic in 6 cases (86%). Five patients were hepatitis C positive (71%). All tumors were surgically removed, with a free resection margin. Among 3 patients with evident vascular invasion, 1 had a positive lymph node. This patient had tumor metastasis 6 years later; otherwise, all patients were disease free on follow-up. Conclusions Our cohort was concordant with published data showing a male predilection, hepatitis C association, and good prognosis when the disease is discovered before metastasis and is surgically excised with negative margins. However, it contradicts the published literature that associates FN-HCC with the absence of advanced fibrosis/cirrhosis.

Abstract Rationale Eosinophilic airway inflammation in COPD is associated with more frequent exacerbations,lower lung function,and corticosteroid responsiveness.DNA methylation captures information about genetic factors and environmental exposures, but is under-studied in eosinophilic COPD.We hypothesized that sputum cell methylation patterns reflect genomic regulation of inflammatory endotypes in COPD by DNA sequence variation. Methods We analyzed DNA previously extracted from induced sputum cells for a prior study(PMID38261629) for which sufficient quantity DNA remained for methylation arrays.For this analysis,we focused on n = 132 SPIROMICS participants with ≥20 pack-years smoking history.Samples were stratified into tertiles based on sputum eosinophil proportions,previously determined from sputum cell differential analysis by the centralized sputum analysis core for SPIROMICS(Univ of North Carolina).We assessed proportion of DNA methylation (β values) spanning 936,866 CpG sites using the Illumina Infinium Methylation EPICv2.0 BeadChip Array,which we transformed into M values(meffil R package). To identify differentially methylated regions (DMRs)(FDR<0.05 in minimum of 2 CpG sites per gene region),we contrasted CpG β values between the high-eosinophil and low-eosinophil tertiles(N = 44 each),using the DMRcate package.We tested for enrichment of genes overlapping with significant DMRs using Enrichr (GWAS Catalog 2025 gene set library).To identify genetic variants associated with DNA methylation levels,we performed Methylation Quantitative Trait Loci (meQTL) analysis using TensorQTL.For each CpG site,we tested associations with SNPs within a ± 500 kb window (cis-meQTL).The linear regression model included age,sex,BMI,smoking status,smoking pack-years,study site,inhaled corticosteroid use, the first two genetic principal components, cell-type proportions (macrophages/monocytes, neutrophils, squamous epithelial cells, lymphocytes), and eosinophil tertile . Significant meQTLs were identified at an FDR<0.05 using Benjamini-Hochberg correction. Results A total of 532 eosinophil-associated DMRs (FDR < 0.05) were identified between the high- and low-eosinophil groups,encompassing 446 unique genes.The top enriched pathways related to counts of eosinophils (adjusted p = 0. 00002464), lymphocytes (adjusted p = 0.0001860), and the sum of eosinophils-plus-basophils (adjusted p = 0.0001860).We identified 18,432 significant SNP-CpG/meQTL pairs (FDR < 0.05),suggesting extensive genetic influence on airway DNA methylation patterns.Among the n = 521 eosinophil-associated CpGs that overlapped with meQTLs,rs55687040 (TENT2,a gene involved in mRNA and miRNA processing) is a GWAS locus for FEV1/FVC ratio (PMID: 26634245), suggesting possible genetic control of airway eosinophilic methylation signatures. Conclusions Our findings disclose distinct DNA methylation signatures associated with sputum eosinophil proportion in COPD.A subset of these CpGs are regulated by genetic variants,suggesting an integrated genetic-epigenetic mechanism underlying airway eosinophilic inflammation with the potential to influence COPD risk and severity. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880, U24 HL141762, R01 HL182622, and R01 HL144718), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan/Viatris.

Abstract Rationale Deficiency of alpha-1 antitrypsin (AAT), the protein encoded by SERPINA1, remains the strongest genetic risk factor for COPD. Individuals heterozygote for the type Z variant, termed the PI*MZ genotype (estimated global prevalence n = 35,000,000), experience varying respiratory morbidity beyond expected from tobacco smoking alone. AAT is a pleiotropic protein which inhibits not only neutrophil elastase but also neutrophil chemotaxis mediated by leukotriene B4 (LTB4) [by antagonizing the LTB4 receptor (LTB4R)] and interleukin-8 (IL-8). Although LTB-4 and IL-8 gene variants and protein levels have independently been implicated in COPD, their potential role in PI*MZ is unknown. Methods COPDGene and SPIROMICS are observational tobacco-smoke and COPD-enriched cohort studies. Participants were phenotyped by spirometry and CT imaging, with whole genome sequencing data available via TOPMed. We analyzed participants with PI*MM (COPDGene n = 9,732; SPIROMICS n = 2,105) and PI*MZ (COPDGene n = 300; SPIROMICS n = 83). LTB-4 (ALOX5AP, LTA4H, LTB4R) and IL-8 (CXCL8, CXCR1, CXCR2) associated gene variants (exonic and intronic) with a minor allele frequency of ≥ 0.05 were extracted. We assessed statistical interactions between MZ status and chest CT outcomes or FEV1% predicted using the SPAGxECCT package with adjustment for relatedness (genetic related matrix) and ancestry (top ten PCs). Baseline protein LTB4R (SPIROMICS only) and IL-8 (both cohorts) protein levels were measured via SomaScan, and statistical interactions between MZ status and AAT concentration were explored. Models were adjusted for age, sex, BMI, smoking status, and pack-years. Given the candidate gene discovery approach, significance was defined as nominal p-value<0.05 Results We identified the following number of variants in genes of the LTB-4 or IL-8 pathways: 87 shared between cohorts; 133 unique to COPDGene; 1 unique to SPIROMICS. LTB-4-related polymorphisms were associated (p < 0.05) with any radiographic outcomes in 22 variants (COPDGene) vs. 23 variants (SPIROMICS), with a single overlap (rs17074984 in ALOX5AP). Two LTB-4-pathway variants were associated with FEV1% predicted in SPIROMICS (both in ALOX5AP), but none in COPDGene. AAT plasma concentrations displayed a statistically significant interaction with FEV1% predicted (p = 0.046) and PRMemphysema (p = 0.013) for LTBR4, but not for IL-8. There was not an interaction by MM/MZ status and protein levels. Conclusions Predominantly LTB-4, and not IL-8, pathway-related genetic variants and protein levels may contribute to disease heterogeneity among PI*MZ individuals. The association of circulating LTB4R protein with reduced lung function, particularly among those with low AAT levels, further suggest interactions between AAT and the leukotriene pathway in PI*MZ individuals. Thus, PI*MZ individuals may uniquely derive benefit from leukotriene-targeting pharmacotherapy. This abstract is funded by: NIH NHLBI K23HL173570

Abstract Background Muscle loss in COPD results from both disuse atrophy and systemic inflammation. We sought to identify inflammatory biomarkers associated with loss of pectoralis muscle area in COPD using serial CT scans and peripheral blood proteomics. Design We analyzed five-year longitudinal data from COPDGene, an ongoing observational cohort of current and former tobacco smokers with or without airflow obstruction. We quantified pectoralis major muscle (PMM) area on chest CT scans using a 3D convolutional neural network (CNN) trained on CT volumes and annotations provided by the TotalSegmentator project. We compared participants with CT PMM data and plasma proteins by SOMAScan (1K platform) from Phase 2 and 3 (paired n = 1,191). The correlation coefficient (r) between longitudinal changes in protein and in PMM area was plotted against the false discovery rate (FDR)-adjusted p-values. Proteins significantly associated with muscle loss (blue) or gain (red) were visualized using volcano plots. We then analyzed a subset (paired n = 500) of individuals with BMI>25 in Phase 2 whose BMI declined in Phase 3. Proteomic models were adjusted for age and clinical center. Pathway analysis utilized G:Profiler. Results Of the participants with paired proteomic and PMM data, mean PMM area was 21.7 ± 17.3 cm² at Phase 2 and 21.3 ± 17.9 cm² at Phase 3, with an annual change in PMM area of -0.31 + 0.99 cm². Multiple proteins were associated with muscle loss from Phase 2 to 3 (including leptin, FABP, and growth hormone receptor) and muscle gain (including F172A, GMEB2, and RNF41) (Fig 1a). Significant pathways were related to cancer, growth factor receptor dysregulation, and PI3K/AKT signaling. When restricting to those with BMI>25 who experienced BMI decline at Phase 3, muscle loss was associated with increased leptin and PACAP, versus association of gain with increased GDF118, EF1β, and FJF6 (Fig 1b). In the entire group, leptin declined between Phase 2 to Phase 3 in n = 571 participants and increased or was unchanged in n = 620. Compared with leptin decline, unchanged or increased leptin was associated with significantly greater interval PMM loss (−2.25 ± 9.75 cm² vs + 0.98 ± 9.43 cm²; p < 0.001) (Fig 1c). Conclusion Loss of PMM over five years was associated with several plasma proteins, including FABP and growth hormone receptor. The top biomarker, leptin, is a pleiotropic adipokine that regulates energy balance and inflammation. Integrating imaging and proteomics may identify future therapeutic targets to mitigate skeletal muscle loss in COPD. This abstract is funded by: This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011

Abstract Background Prostaglandin E2 (PGE2) exerts paradoxical effects in asthma, acting as both a protective mediator and a contributor to pathology depending on context. Its role is shaped by type 2 (T2)-status, eosinophilia, and exacerbation frequency. In epithelial cell cultures from asthmatic and healthy individuals, interleukin (IL)-13 suppresses PGE2 synthesis genes (PTGS2 and PGES) while upregulating HPGD, which encodes for the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase (15-PGDH) (PMID:16751012), suggesting diminished PGE2 availability during T2 inflammation. Similarly, in aspirin-exacerbated respiratory disease (AERD), impaired cyclooxygenase disrupts PGE2 biosynthesis, fueling unchecked leukotriene production and eosinophilic inflammation (PMID: 30516547), underscoring PGE2’s protective role in limiting disease progression. Conversely, in nasal polyps, tuft cells are activated by IL-13 to produce PGE2 (PMID: 35608904), highlighting PGE2’s potential pathogenicity. Objective To assess associations between PGE2-pathway gene expression in bronchial brushings and asthma severity, and to determine how nasal polyp history modifies these relationships. Methods We analyzed bronchial epithelial brushings from 109 adults with asthma (mean age 42.4±12.1, 64% female, 52% severe asthma, 18% nasal polyps) using normalized and batch-corrected RNA-seq data from the baseline visit in the Severe Asthma Research Program (SARP)3 (PMID: 36796454). Age-adjusted and nasal polyp-adjusted relationships were calculated between ratios of PGE2 synthesis and metabolism genes and clinical outcomes (ASSESS score, FEV1 %predicted). The composite PGE2 score (PMID: 35608904), derived from nasal polyp analysis, was calculated from the average scaled log-normalized expression of six PGE2-responsive genes. All data were analyzed using a linear regression mixed model with a random effect for site. Results Ratios of PGE2 synthesis genes (PTGS1/2, PTGES2) to HPGD were significantly associated with greater disease severity (change in ASSESS Score) (Fig.1A, solid lines) and lower lung function (change in FEV1 %predicted) (Fig.1B, solid lines). These relationships persisted after adjusting for nasal polyps (Fig.1, dashed lines). The composite PGE2 score was also related to disease severity (Fig.1A, black solid line) but attenuated when nasal polyps were accounted for (Fig.1A, black dashed lines). Interestingly, lower lung function remained associated with the PGE2 score even after nasal polyp adjustment (Fig.1B, dashed black lines). Conclusions Our analysis demonstrates that the balance between PGE2 synthesis and degradation in the bronchial epithelium is closely linked to asthma severity and lung function, independent of nasal polyp status. Future work will integrate transcriptomic and clinical data longitudinally to establish whether PGE2 could serve as a biomarker for asthma trajectory. This abstract is funded by: HL115118 (LCD), U10HL109152 (S.E.W.), U10HL109172 (to E.I. and B.D.L), U10HL109168 (N.N.J.), U10HL109250 (S.C.E), U10HL109164 (W.C.M), U10HL109257 (M.C), and U10HL109146 (to P.G.W. and S.A.C.)