Louise V. Wain

Extract Previous genome-wide association studies (GWAS) of idiopathic pulmonary fibrosis (IPF) have identified 35 common genetic risk loci associated with IPF susceptibility [1, 2]. However, these studies have been conducted in cohorts predominantly of European genetic ancestry. There have been two genome-wide association studies in East Asian populations, which suggest that genetic variants associated with IPF in European individuals are also associated in this population (PMIDs: 18835860, 42085270). A recent multi-ancestry GWAS for IPF has been conducted by Partanen et al. [1], however this used cases defined using electronic health records which often lead to imprecise effect estimates for IPF [3].

Background: Acute COVID-19 alters the airway microbiota. Whether these changes persist post-COVID-19 and contribute to long COVID is unknown. We aimed to describe the microbiota by long COVID severity and subtype, and identify links with inflammation. Methods: Adults were prospectively recruited to the longitudinal UK Post-hospitalisation COVID-19 study (PHOSP-COVID). Patients were grouped by previously described “severity clusters” (of ongoing health impairments) and symptom subgroups. Oral and sputum microbiota (at 6 months post-discharge) were characterised through 16S ribosomal RNA gene amplicon sequencing, and microbiota diversity was assessed. Co-occurrence network analysis identified keystone taxa. Associations between keystone taxa and plasma inflammatory proteins were assessed through Spearman's rank correlations. Results: 771 participants had their microbiota assessed. Of participants with oral rinses and “severity cluster” assignment (mean age 57.5 years), 278 out of 722 (38.5%) were women. The “very severe” cluster, in which disease was predominantly pulmonary in nature, was associated with a distinct microbiota profile post-COVID-19. Reduced lung function was associated with a distinct oral microbiota profile. Persistent neurocognitive symptoms were associated with a distinct oral microbiota profile, while gastrointestinal symptoms were associated with a distinct sputum microbiota profile. Microbiota keystone taxa shifted to a higher prevalence of lactic acid bacteria associated with worse health outcomes. Lactic acid bacteria abundance was associated with elevated blood inflammatory proteins. Conclusion: Distinct oral and sputum microbiota profiles were associated with pulmonary function and with neurocognitive and gastrointestinal symptoms in long COVID. Shifts in keystone microbiota taxa linked with inflammation, based on worse health outcomes, suggest a potential role change for lactic acid bacteria, which may be associated with the host immune response.

Background: Fibrotic interstitial lung disease (fILD) is often diagnosed late and can be difficult to recognise in people with common respiratory or cardiac long-term conditions. We examined whether baseline routine blood-test profiles and leucocyte telomere length (LTL) identified groups at higher risk of subsequent hospital-recorded fILD among people with COPD, asthma or heart failure. Methods: We analysed 396 516 UK Biobank participants with complete baseline C-reactive protein, albumin, haemoglobin, platelet count, estimated glomerular filtration rate, LTL and core covariates. The primary outcome was first post-baseline hospital recording of ICD-10 J84.1; other coded ILD diagnoses and death were treated as competing events. Cause-specific Cox models assessed associations and discrimination. Risk-enrichment analyses included 53 661 participants with pre-baseline COPD, asthma or heart failure. Results: Adding the biomarker panel improved the C-index from 0.783 to 0.803; the combined model reached 0.816. Among participants with at least two of four prespecified abnormal blood-test results and shortest-decile LTL, 10-year fILD cumulative incidence was 5.00% (14/280; 95% CI 2.50–7.50%), versus 0.43% (201/46 474; 0.38–0.49%) in the reference group. Elevated risk persisted beyond two years of follow-up. Adverse biomarker/LTL profiles were disproportionately represented among more deprived participants; fILD incidence was 0.50% versus 0.85% in the least versus most deprived quintiles, while competing mortality was 4.70% versus 10.78%. Conclusions: Routine blood-test profiles and LTL identified groups at increased risk of subsequent hospital-recorded fILD among people with COPD, asthma or heart failure. These findings support long-term risk enrichment and require external clinical validation before use in diagnostic pathways.

Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFFPR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performancewas evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong’s test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Findings: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient’s personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong’s test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong’s test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Interpretation: Incorporating IPF-PRS into a model based on the patient’s clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.

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.

Extract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease thought to result from an aberrant response to lung injury, culminating in an exaggerated healing response with excessive deposition of extracellular matrix in the interstitium [1].

Background: Despite multiple clinical trials, disease-modifying treatments for COPD are currently limited. Since many drugs target proteins, identifying causality between proteins and lung function informs understanding of COPD pathophysiology and may suggest novel targets. We used Mendelian randomisation (MR) to prioritise proteins as potentially causal for lung function. For prioritised proteins, we explored their potential suitability as drug targets by predicting their effects on a range of clinical outcomes. Methods: We used genome-wide association study (GWAS) data on 2923 proteins (N=48 195, UK Biobank) to identify single genetic variants (cis-pQTLs) associated with protein levels (P≤5×10 ⁻⁹ , variant ≤100 kb of a transcription start site). We performed cis-pQTL-MR analyses of four spirometric traits (N=149 166, 36 independent cohorts). Sensitivity analyses included colocalisation and reverse direction MR. We report associations between cis-pQTLs for prioritised proteins and multiple clinical respiratory outcomes, and use phenome-wide analysis to explore potential adverse effects or drug repurposing opportunities. Findings: 1841 proteins had a suitable cis-pQTL. We implicated 16 proteins as potentially causal for lung function (p−5 ): six proteins have not been implicated by previous lung function GWAS or MR (DTD1, PILRA, PTPRK, TDRKH, GRHPR, NUDT5), and we provide corroborative evidence for 10 proteins. We add to the literature identifying surfactant protein D (SFTPD) as a candidate, yet predict that integrin subunit alpha V (ITGAV) inhibition could impair some lung function measures, mimicking adverse results from a recent trial. Interpretation: Our approach identifies proteins (some novel) which are potentially therapeutic targets for respiratory disease, and which warrant follow-up for utility and safety.

Background: Physical inactivity is a risk factor for severe COVID-19 and often worsens after hospitalisation. Clinicians need quick, accurate assessments to target interventions. We aimed to assess the validity of the General Practice Physical Activity Questionnaire (GPPAQ) in adults recovering one year after COVID-19 hospitalisation . Methods: Post-hospitalisation for COVID-19, adults attended a one-year-visit and completed the GPPAQ Physical Activity Index (PAI-4 active), 14-day wrist-worn accelerometry (Moderate-Vigorous PA [MVPA]- active), and other health outcomes. Validity was examined via : (i) internal consistency (factor analysis); (ii) measurement invariance across sex, age, and ethnicity using differential item functioning (DIF); (iii) convergent validity (GPPAQ sensitivity/specificity versus accelerometry); and (iv) construct validity (correlations with health outcomes). Results: 752 participants had GPPAQ and accelerometry (265 female, mean± sd age 60.9±11.6 years, MVPA 18.75 min·day ⁻¹ (IQR 7.55, 36.11), PAI-1 46.8%, PAI-2 15.6%, PAI-3 19.4%, PAI-4 18.2%. Factor analyses supported good internal consistency with two factors (daily activities, physical exercise). Confirmatory factor Index (CFI) showed excellent fit (CFI 0.965). DIF indicated moderate variability by sex and age. GPPAQ-PAI showed limited sensitivity (26.3%) for correctly classifying physically active individuals, but higher specificity (88.4%) for classifying physical inactivity, and weak-to-moderate correlations with health outcomes. Conclusions: GPPAQ demonstrates internal consistency, with construct and convergent validity in adults 1-year post-COVID-19 hospitalisation. GPPAQ effectively identifies inactive individuals to support clinical care; however, its sensitivity suggests underestimation of activity relative to accelerometry. Future pathways should combine GPPAQ with device-based assessment to optimise evaluation of physical activity to guide pulmonary rehabilitation and targeted interventions.

Background: In approximately 10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. Methods: We used electronic healthcare records (EHR) linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10 ⁻⁶ ) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. Results: In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher BMI compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence ( BACH2 , D2HGDH , IL1RL1 , RPS26 , SMAD3 ). Conclusion: We present the first use of EHR in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Extract Idiopathic pulmonary fibrosis (IPF) is a poorly understood chronic lung disease characterised by progressive fibrosis, with poor survival and limited treatment options. IPF is thought to result from an aberrant response to lung injury, culminating in an exaggerated healing response with excessive deposition of extracellular matrix in the interstitium [1]. Genetic studies have emphasised high heritability and common polygenic aetiology in the development of IPF. There are more than 30 replicated common genetic signals associated with IPF [1] implicating genes involved in host defence, cell proliferation and signalling among others.