Imperial College London

DrPhilipMolyneaux

Faculty of MedicineNational Heart & Lung Institute

Reader in Interstitial Lung Disease
 
 
 
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p.molyneaux

 
 
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Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

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108 results found

McErlean P, Bell CG, Hewitt RJ, Busharat Z, Ogger PP, Ghai P, Albers GJ, Calamita E, Kingston S, Molyneaux PL, Beck S, Lloyd CM, Maher TM, Byrne AJet al., 2021, DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis., Am J Respir Crit Care Med

RATIONALE: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge of epigenetics of AMs in IPF are limited. METHODS: We undertook DNA methylation profiling using Illumina EPIC (850k) arrays in sorted AMs from Healthy (n=14) and IPF (n=30) donors. Cell-type deconvolution was performed using reference myeloid-cell DNA methylomes. MEASUREMENTS AND MAIN RESULTS: Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF-AMs. DNAm 'clock' analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKFB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. CONCLUSIONS: Collectively, our data identify that changes in the epigenome are associated with development and function of AMs in the IPF lung.

Journal article

Juan Guardela BM, Sun J, Zhang T, Xu B, Balnis J, Huang Y, Ma S-F, Molyneaux PL, Maher TM, Noth I, Michaud G, Jaitovich A, Herazo-Maya JDet al., 2021, 50-gene risk profiles in peripheral blood predict COVID-19 outcomes: A retrospective, multicenter cohort study, EBioMedicine, Vol: 69, ISSN: 2352-3964

BACKGROUND: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated. METHODS: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts. FINDINGS: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4+, CD8+ T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts. INTERPRETATION: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases.

Journal article

Kreuter M, Lee JS, Tzouvelekis A, Oldham JM, Molyneaux PL, Weycker D, Atwood M, Kirchgaessler K-U, Maher TMet al., 2021, Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 74-81, ISSN: 1073-449X

Rationale: There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. Objectives: We used pooled data from pirfenidone and interferon gamma-1b trials to explore the association between monocyte count and prognosis in patients with IPF. Methods: This retrospective pooled analysis included patients (active and placebo arms) from four Phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in percent predicted forced vital capacity, ≥50 m decline in 6-minute walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. Measurements and Main Results: This analysis included 2067 patients stratified by monocyte count (at baseline: <0.60 GI/L [n=1609], 0.60–<0.95 GI/L [n=408], and ≥0.95 GI/L [n=50]). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60–<0.95 GI/L or ≥0.95 GI/L versus <0.60 GI/L experienced IPF progression (p=0.016 and p=0.002, respectively), all-cause hospitalization (p=0.030 and p=0.003, respectively), and all cause mortality (p=0.005 and p<0.001, respectively) over 1 year. Change in monocyte count from baseline was not associated with any of the outcomes over 1 year and did not appear to be affected by study treatment. Conclusions: In patients with IPF, elevated monocyte count was associated with increased risks of IPF progression, hospitalization, and mortality. Monocyte count may provide a simple and inexpensive prognostic biomarker in IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (h

Journal article

Trachalaki A, Tsitoura E, Mastrodimou S, Invernizzi R, Vasarmidi E, Bibaki E, Tzanakis N, Molyneaux PL, Maher TM, Antoniou Ket al., 2021, Enhanced IL-1β Release Following NLRP3 and AIM2 Inflammasome Stimulation Is Linked to mtROS in Airway Macrophages in Pulmonary Fibrosis, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224

Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1β release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1β release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1β release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1β release and AIM2 and IL-18 relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.

Journal article

Nolan CM, Patel S, Barker RE, Walsh JA, Polgar O, Maddocks M, George PM, Renzoni EA, Wells AU, Molyneaux PL, Kouranos V, Chua F, Maher TM, Man WD-Cet al., 2021, Muscle stimulation in advanced idiopathic pulmonary fibrosis: a randomised placebo-controlled feasibility study., BMJ Open, Vol: 11, Pages: 1-11, ISSN: 2044-6055

OBJECTIVES: To assess the acceptability of neuromuscular electrical stimulation (NMES) of the quadriceps muscles in people with idiopathic pulmonary fibrosis (IPF) and to identify whether a future definitive trial is feasible. DESIGN: A randomised, parallel, two-group, participant and assessor-blinded, placebo-controlled feasibility trial with embedded qualitative interviews. SETTING: Outpatient department, Royal Brompton and Harefield Hospitals. PARTICIPANTS: Twenty-two people with IPF: median (25th, 75th centiles) age 76 (74, 82) years, forced vital capacity 62 (50, 75) % predicted, 6 min walk test distance 289 (149, 360) m. INTERVENTIONS: Usual care (home-based exercise, weekly telephone support, breathlessness management leaflet) with either placebo or active NMES for 6 weeks, with follow-up at 6 and 12 weeks. PRIMARY OUTCOME MEASURES: Feasibility of recruitment and retention, treatment uptake and adherence, outcome assessments, participant and outcome assessor blinding and adverse events related to interventions. SECONDARY OUTCOME MEASURES: Outcome measures with potential to be primary or secondary outcomes in a definitive clinical trial. In addition, purposively sampled participants were interviewed to capture their experiences and acceptability of the trial. RESULTS: Out of 364 people screened, 23 were recruited: 11 were allocated to each group and one was withdrawn prior to randomisation. Compared with the control group, a greater proportion of the intervention group completed the intervention, remained in the trial blinded to group allocation and experienced intervention-related adverse events. Assessor blinding was maintained. The secondary outcome measures were feasible with most missing data associated with the accelerometer. Small participant numbers precluded identification of an outcome measure suitable for a definitive trial. Qualitative findings demonstrated that trial process and active NMES were acceptable but there were concerns abo

Journal article

Myall KJ, Molyneaux PL, West AG, authorset al., 2021, Reply: A role for steroids in COVID-19 associated pneumonitis at six-week follow-up?, Annals of the American Thoracic Society, Vol: 18, Pages: 1083-1084, ISSN: 1546-3222

Journal article

Myall KJ, Mukherjee B, Castanheira AM, Lam JL, Benedetti G, Mak SM, Preston R, Thillai M, Dewar A, Molyneaux PL, West AGet al., 2021, Persistent post-COVID-19 interstitial lung disease: an observational study of corticosteroid treatment, Annals of the American Thoracic Society, Vol: 18, Pages: 799-806, ISSN: 2329-6933

RATIONALE: The natural history of recovery from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) remains unknown. Since fibrosis with persistent physiological deficit is a previously-described feature of patients recovering from similar coronaviruses, treatment represents an early opportunity to modify the disease course, potentially preventing irreversible impairment. OBJECTIVES: Determine the incidence of and describe the progression of persistent inflammatory interstitial lung disease (ILD) following SARS-CoV2 when treated with prednisolone. METHODS: A structured assessment protocol screened for sequelae of SARS-CoV2 pneumonitis. 837 patients were assessed by telephone four weeks after discharge. Those with ongoing symptoms had outpatient assessment at six weeks. Thirty patients diagnosed with persistent interstitial lung changes at multi-disciplinary team meeting were reviewed in the interstitial lung disease service and offered treatment. These patients had persistent, non-improving symptoms. RESULTS: At four weeks post-discharge, 39% of patients reported ongoing symptoms (325/837), and were assessed. Interstitial lung disease, predominantly organising pneumonia, with significant functional deficit was observed in 35/837 survivors (4.8%). Thirty of these patients received steroid treatment, resulting in a mean relative increase in transfer factor following treatment of 31.6% (standard deviation ± 27.64, p <0.001), and FVC of 9.6% (standard deviation ± 13.01, p = 0.014), with significant symptomatic and radiological improvement. CONCLUSION: Following SARS-CoV-2 pneumonitis, a cohort of patients are left with both radiological inflammatory lung disease and persistent physiological and functional deficit. Early treatment with corticosteroids was well tolerated and associated with rapid and significant improvement. This preliminary data should inform further study into the natural history and potential treatment for patients with persist

Journal article

Stock CJW, Hoyles RK, Daccord C, Kokosi M, Visca D, De Lauretis A, Alfieri V, Kouranos V, Margaritopoulos G, George PM, Molyneaux PL, Chua F, Maher TM, Abraham DJ, Ong V, Donovan J, Sestini P, Denton CP, Wells AU, Renzoni EAet al., 2021, Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression, Respirology, Vol: 26, Pages: 461-468, ISSN: 1323-7799

Background and objectiveThe course of systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is highly variable, and accurate prognostic markers are needed. KL‐6 is a mucin‐like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21‐1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury.MethodsSerum KL‐6 and CYFRA 21‐1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed‐effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis.ResultsIn both cohorts, KL‐6 and CYFRA 21‐1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL‐6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc‐ILD, serum KL‐6, but not CYFRA 21‐1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL‐6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage.ConclusionOur results suggest serum KL‐6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc‐ILD.

Journal article

Dhindsa RS, Mattsson J, Nag A, Wang Q, Wain L, Allen R, Wigmore EM, Ibanez K, Vitsios D, Deevi SVV, Wasilewski S, Karlsson M, Lassi G, Olsson H, Muthas D, Monkley S, Mackay A, Murray L, Young S, Haefliger C, Maher TM, Belvisi MG, Jenkins G, Molyneaux PL, Platt A, Petrovski Set al., 2021, Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis, Communications Biology, Vol: 4, ISSN: 2399-3642

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87, 95% confidence interval: 2.03–4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10−20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

Journal article

Chua F, Vancheeswaran R, Draper A, Vaghela T, Knight M, Mogal R, Singh J, Spencer LG, Thwaite E, Mitchell H, Calmonson S, Mahdi N, Assadullah S, Leung M, O'Neill A, Popat C, Kumar R, Humphries T, Talbutt R, Raghunath S, Molyneaux PL, Schechter M, Lowe J, Barlow Aet al., 2021, Early prognostication of COVID-19 to guide hospitalisation versus outpatient monitoring using a point-of-test risk prediction score, Thorax, Vol: 76, Pages: 696-703, ISSN: 0040-6376

INTRODUCTION: Risk factors of adverse outcomes in COVID-19 are defined but stratification of mortality using non-laboratory measured scores, particularly at the time of prehospital SARS-CoV-2 testing, is lacking. METHODS: Multivariate regression with bootstrapping was used to identify independent mortality predictors in patients admitted to an acute hospital with a confirmed diagnosis of COVID-19. Predictions were externally validated in a large random sample of the ISARIC cohort (N=14 231) and a smaller cohort from Aintree (N=290). RESULTS: 983 patients (median age 70, IQR 53-83; in-hospital mortality 29.9%) were recruited over an 11-week study period. Through sequential modelling, a five-predictor score termed SOARS (SpO2, Obesity, Age, Respiratory rate, Stroke history) was developed to correlate COVID-19 severity across low, moderate and high strata of mortality risk. The score discriminated well for in-hospital death, with area under the receiver operating characteristic values of 0.82, 0.80 and 0.74 in the derivation, Aintree and ISARIC validation cohorts, respectively. Its predictive accuracy (calibration) in both external cohorts was consistently higher in patients with milder disease (SOARS 0-1), the same individuals who could be identified for safe outpatient monitoring. Prediction of a non-fatal outcome in this group was accompanied by high score sensitivity (99.2%) and negative predictive value (95.9%). CONCLUSION: The SOARS score uses constitutive and readily assessed individual characteristics to predict the risk of COVID-19 death. Deployment of the score could potentially inform clinical triage in preadmission settings where expedient and reliable decision-making is key. The resurgence of SARS-CoV-2 transmission provides an opportunity to further validate and update its performance.

Journal article

Huang Y, Oldham JM, Ma S-F, Unterman A, Liao S-Y, Barros AJ, Bonham CA, Kim JS, Vij R, Adegunsoye A, Strek ME, Molyneaux PL, Maher TM, Herazo-Maya JD, Kaminski N, Moore BB, Martinez FJ, Noth Iet al., 2021, Blood transcriptomic predicts progression of pulmonary fibrosis and associates natural killer cells., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 197-208, ISSN: 1073-449X

Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objective: To identify a predictor using short-term longitudinal changes in gene-expression that forecasts future forced vital capacity (FVC) decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from Correlating Outcomes with biochemical Markers to Estimate Time-progression in IPF (COMET) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months, and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC-predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-seq (PBMC scRNA-seq) data from healthy controls were used as references to characterize cell type compositions from bulk PBMC RNA-seq data that were associated with FVC decline. Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared to a cross-sectional model. The FVC-predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were down- and up-regulated, respectively. Cellular deconvolution using scRNA-seq data identified natural killer (NK) cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. Analysis of cell types involved in the progressor signature supports the novel involvement of NK cells in IPF progression.

Journal article

Simpson T, Barratt SL, Beirne P, Chaudhuri N, Crawshaw A, Crowley LE, Fletcher S, Gibbons MA, Hallchurch P, Horgan L, Jakaityte I, Lewis T, McLellan T, Myall KJ, Miller R, Smith DJF, Stanel S, Thillai M, Thompson F, Wallis T, Wu Z, Molyneaux PL, West AGet al., 2021, The burden of Progressive Fibrotic Interstitial lung disease across the UK., European Respiratory Journal, Vol: 58, Pages: 1-4, ISSN: 0903-1936

Journal article

Molyneaux PL, 2021, The microbiome in IPF: tissue is not the issue., Thorax, Vol: 76, Pages: 218-218, ISSN: 0040-6376

Journal article

Invernizzi R, Wu BG, Barnett J, Ghai P, Kingston S, Hewitt RJ, Feary J, Li Y, Chua F, Wu Z, Wells AU, George PM, Renzoni EA, Nicholson AG, Rice A, Devaraj A, Segal LN, Byrne AJ, Maher TM, Lloyd CM, Molyneaux PLet al., 2021, The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis., Am J Respir Crit Care Med, Vol: 203, Pages: 339-347

Rationale: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP.Objectives: To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects.Methods: We prospectively recruited individuals with a CHP diagnosis (n = 110), individuals with an IPF diagnosis (n = 45), and control subjects (n = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways.Measurements and Main Results: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. However, in IPF, Firmicutes dominated, whereas the percentage of reads assigned to Proteobacteria in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the Staphylococcus burden was increased in CHP, and Actinomyces and Veillonella burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP.Conclusions: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.

Journal article

Leavy OC, Ma S-F, Molyneaux PL, Maher TM, Oldham JM, Flores C, Noth I, Jenkins RG, Dudbridge F, Wain LV, Allen RJet al., 2020, Proportion of idiopathic pulmonary fibrosis risk explained by known Common genetic loci in European populations, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 775-778, ISSN: 1073-449X

Journal article

Hirani N, MacKinnon AC, Nicol L, Ford P, Schambye H, Pedersen A, Nilsson UJ, Leffler H, Sethi T, Tantawi S, Gavelle L, Slack RJ, Mills R, Karmakar U, Humphries D, Zetterberg F, Keeling L, Paul L, Molyneaux PL, Li F, Funston W, Forrest IA, Simpson AJ, Gibbons MA, Maher TMet al., 2020, Target-inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis., European Respiratory Journal, Vol: 57, Pages: 1-13, ISSN: 0903-1936

Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small molecule inhibitor of Gal-3.A randomised, double-blind, multi-centre, placebo-controlled, phase I/IIa study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF (NCT02257177). Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15 mg to 50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once daily doses of TD139 (0.3 mg to 10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side effects. TD139 was rapidly absorbed, with mean Tmax values ranging from 0.6 h to 3 h and a T½ of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 mg and 10 mg dose groups compared to placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (PDGF-BB, PAI-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on BAL macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.

Journal article

Ogger PP, Albers GJ, Hewitt RJ, O'Sullivan BJ, Powell JE, Calamita E, Ghai P, Walker SA, McErlean P, Saunders P, Kingston S, Molyneaux PL, Halket JM, Gray R, Chambers DC, Maher TM, Lloyd CM, Byrne AJet al., 2020, Itaconate controls the severity of pulmonary fibrosis, Science Immunology, Vol: 5, Pages: 1-13, ISSN: 2470-9468

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

Journal article

Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, Babu S, Barber CM, Barratt S, Bendstrup E, Bianchi S, Castillo Villegas D, Chaudhuri N, Chua F, Coker R, Chang W, Crawshaw A, Crowley LE, Dosanjh D, Fiddler CA, Forrest IA, George PM, Gibbons MA, Groom K, Haney S, Hart SP, Heiden E, Henry M, Ho L-P, Hoyles RK, Hutchinson J, Hurley K, Jones MG, Jones S, Kokosi M, Kreuter M, Mackay LS, Mahendran S, Margaritopoulos G, Molina-Molina M, Molyneaux PL, O'Brien A, O'Reilly K, Packham A, Parfrey H, Poletti V, Porter JC, Renzoni E, Rivera-Ortega P, Russell A-M, Saini G, Spencer LG, Stella GM, Stone H, Sturney S, Thickett D, Thillai M, Wallis T, Ward K, Wells AU, West A, Wickremasinghe M, Woodhead F, Hearson G, Howard L, Baillie JK, Openshaw PJM, Semple MG, Stewart I, Jenkins RG, ISARIC4C Investigatorset al., 2020, Outcome of hospitalization for COVID-19 in patients with interstitial lung disease: an international multicenter study., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 1656-1665, ISSN: 1073-449X

RATIONALE: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. OBJECTIVES: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. METHODS: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. MEASUREMENTS AND MAIN RESULTS: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39-3.71). CONCLUSIONS: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal article

Stock CJ, Conti C, Montero-Fernandez Á, Caramori G, Molyneaux PL, George PM, Kokosi M, Kouranos V, Maher TM, Chua F, Rice A, Denton CP, Nicholson AG, Wells A, Sestini P, Renzoni EAet al., 2020, Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?, Thorax, Vol: 75, Pages: 901-903, ISSN: 0040-6376

The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.

Journal article

Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL, Jordan S, Lim E, Lang-Lazdunski L, Begum S, Dusmet M, Anikin V, Beddow E, Finch J, Asadi N, Popat S, Le Quesne J, Husain AN, Cookson WO, Moffatt MF, Nicholson AGet al., 2020, Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade, Histopathology, Vol: 77, Pages: 423-436, ISSN: 0309-0167

AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (1) externally validate the prognostic role of pleomorphic features in E-MPM and (2) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared those without (5.4 months vs 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 months vs. 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

Journal article

George PM, Spagnolo P, Kreuter M, Altinisik G, Bonifazi M, Martinez FJ, Molyneaux PL, Renzoni EA, Richeldi L, Tomassetti S, Valenzuela C, Vancheri C, Varone F, Cottin V, Costabel U, Erice ILD working groupet al., 2020, Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities., The Lancet Respiratory Medicine, Vol: 8, Pages: 925-934, ISSN: 2213-2600

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.

Journal article

Molyneaux PL, Smith JJ, Saunders P, Chua F, Wells AU, Renzoni EA, Nicholson AG, Fahy WA, Jenkins RG, Maher TMet al., 2020, Bronchoalveolar lavage is safe and well tolerated in individuals with idiopathic pulmonary fibrosis: an analysis of the PROFILE study, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 136-139, ISSN: 1073-449X

Journal article

Leavy OC, Ma S-F, Molyneaux PL, Maher TM, Oldham JM, Flores C, Noth I, Jenkins RG, Dudbridge F, Wain LV, Allen RJet al., 2020, Proportion of idiopathic pulmonary fibrosis risk explained by known genetic loci, Publisher: medRxiv

Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

Working paper

Barnes H, Morisset J, Molyneaux P, Westall G, Glaspole I, Collard HR, CHP Exposure Assessment Collaboratorset al., 2020, A systematically derived exposure assessment instrument for Chronic Hypersensitivity Pneumonitis, Chest, Vol: 157, Pages: 1506-1512, ISSN: 0012-3692

BACKGROUND: Chronic hypersensitivity pneumonitis (CHP) is an immune mediated interstitial lung disease, caused by inhalational exposure to environmental antigens, resulting in parenchymal fibrosis. By definition, a diagnosis of CHP assumes a history of antigen exposure, but only half of all patients eventually diagnosed with CHP will have a causative antigen identified. Individual clinician variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis. METHODS: A list of potential causative exposures were derived from a systematic review of the literature. A Delphi method was applied to an international panel of ILD experts, to obtain consensus regarding technique for the elicitation of exposure to antigens relevant to a diagnosis of CHP. The consensus threshold was set at 80% agreement, and median ≤ 2, IQR = 0 on a five-point Likert scale (1: strongly agree, 2: tend to agree, 3: neither agree nor disagree, 4: disagree, 5: strongly disagree). RESULTS: In two rounds, 36/40 experts participated. Experts agreed on 18 exposure items to ask every patient with suspected CHP. Themes included CHP inducing exposures, features that contribute to an exposure's relevance, and quantification of a relevant exposure. Based on the results from the literature review and Delphi process, a CHP exposure assessment instrument was derived. Using cognitive interviews, the instrument was revised by ILD patients for readability and usability. CONCLUSIONS: This Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP and provides basis for a systematically derived CHP exposure assessment instrument. Clinical utility of this exposure assessment instrument may be affected by different local prevalence patterns of exposures. Ongoing research is required to clinically validate these items and consider their impact in more geographically diverse settings.

Journal article

Invernizzi R, Lloyd CM, Molyneaux PL, 2020, Respiratory microbiome and epithelial interactions shape immunity in the lungs, Immunology, Vol: 160, Pages: 171-182, ISSN: 0019-2805

The airway epithelium represents a physical barrier to the external environment acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens. However, lung epithelial cells are increasingly recognised as active effectors of microbial defence, contributing to both innate and adaptive immune function in the lower respiratory tract. These cells express an ample repertoire of pattern-recognition receptors with specificity for conserved microbial and host motifs. Modern molecular techniques have uncovered the complexity of the lower respiratory tract microbiome. The interaction between the microbiota and the airway epithelium is key to understanding how stable immune homeostasis is maintained. Loss of epithelial integrity following exposure to infection can result in the onset of inflammation in susceptible individuals and may culminate in lung disease. Here we discuss the current knowledge regarding the molecular and cellular mechanisms by which the pulmonary epithelium interacts with the lung microbiome in shaping immunity in the lung. Specifically, we focus on the interactions between the lung microbiome and the cells of the conducting airways in modulating immune cell regulation and how defects in barrier structure and function may culminate in lung disease. Understanding these interactions is fundamental in the search for more effective therapies for respiratory diseases.

Journal article

Invernizzi R, Barnett J, Rawal B, Nair A, Ghai P, Kingston S, Chua F, Wu Z, Wells A, Renzoni E, Nicholson A, Rice A, Lloyd C, Byrne A, Maher T, Devaraj A, Molyneaux Pet al., 2020, Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent, European Respiratory Journal, Vol: 55, Pages: 1-9, ISSN: 0903-1936

Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.Increased bacterial burden significantly associated with disease progression (hazard ratio 2.1; 95% confidence interval 1.287–3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.

Journal article

Stock CJW, De Lauretis A, Visca D, Daccord C, Kokosi M, Kouranos V, Margaritopoulos G, George PM, Molyneaux PL, Nihtyanova S, Chua F, Maher TM, Ong V, Abraham DJ, Denton CP, Wells AU, Wain LV, Renzoni EAet al., 2020, Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease, Clinical Rheumatology, Vol: 39, Pages: 1173-1179, ISSN: 0770-3198

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr = 6.6 × 10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.&b

Journal article

Maher TM, Simpson JK, Porter JC, Wilson FJ, Chan R, Eames R, Cui Y, Siederer S, Parry S, Kenny J, Slack RJ, Sahota J, Paul L, Saunders P, Molyneaux PL, Lukey PT, Rizzo G, Searle GE, Marshall RP, Saleem A, Kang'ombe AR, Fairman D, Fahy WA, Vahdati-Bolouri Met al., 2020, A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor, Respiratory Research, Vol: 21, ISSN: 1465-9921

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF.MethodsThis was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%.ResultsEight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: − 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination.ConclusionsThis study demonstrated engagement of th

Journal article

Allen RJ, Guillen-Guio B, Oldham JM, Ma S-F, Dressen A, Paynton ML, Kraven LM, Obeidat M, Li X, Ng M, Braybrooke R, Molina-Molina M, Hobbs BD, Putman RK, Sakornsakolpat P, Booth HL, Fahy WA, Hart SP, Hill MR, Hirani N, Hubbard RB, McAnulty RJ, Millar AB, Navaratnam V, Oballa E, Parfrey H, Saini G, Whyte MKB, Zhang Y, Kaminski N, Adegunsoye A, Strek ME, Neighbors M, Sheng XR, Gudmundsson G, Gudnason V, Hatabu H, Lederer DJ, Manichaikul A, Newell Jr JD, O'Connor GT, Ortega VE, Xu H, Fingerlin TE, Bossé Y, Hao K, Joubert P, Nickle DC, Sin DD, Timens W, Furniss D, Morris AP, Zondervan K, Hall IP, Sayers I, Tobin MD, Maher TM, Cho MH, Hunninghake GM, Schwartz DA, Yaspan BL, Molyneaux PL, Flores C, Noth I, Jenkins RG, Wain LVet al., 2020, Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 564-574, ISSN: 1073-449X

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results: We identified and replicated three new genome-wide significant (P<5×10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Journal article

Carney SM, Clemente JC, Cox MJ, Dickson RP, Huang YJ, Kitsios GD, Kloepfer KM, Leung JM, LeVan TD, Molyneaux PL, Moore BB, O'Dwyer DN, Segal LN, Garantziotis S, ATS Allergy, Immunology and Inflammation Assembly Working Group on Microbiome in Lung Diseaseet al., 2020, Methods in lung microbiome research., American Journal of Respiratory Cell and Molecular Biology, Vol: 62, Pages: 283-299, ISSN: 1044-1549

The lung microbiome is associated with host immune response and health outcomes in experimental models and patient cohorts. Lung microbiome research is increasing in volume and scope; however, there are no established guidelines for study design, conduct and reporting of lung microbiome studies. Standardized approaches to yield reliable and reproducible data that can be synthesized across studies, will ultimately improve the scientific rigor and impact of published work and greatly benefit microbiome research. In this review, we identify and address several key elements of microbiome research: conceptual modeling and hypothesis framing, study design, experimental methodology and pitfalls, data analysis and reporting considerations. Finally, we explore possible future directions and research opportunities. Our goal is to aid investigators who are interested in this burgeoning research area and will hopefully provide the foundation for formulating consensus approaches in lung microbiome research.

Journal article

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