Biology subjects

Maher, T. M.

Publications and source records attributed to Maher, T. M..

7 recordsLinked to original sources

bioRxiv2024

Genetic burden of dysregulated cytoskeletal organisation in the pathogenesis of pulmonary fibrosis

BackgroundRare genetic variants contribute to pulmonary fibrosis (PF) risk and outcome, with known variants highlighting the importance of impaired telomere maintenance and surfactant biology. However, much of the disrupted genetic architecture of PF remains unexplained. This study aimed to identify genes with rare pathogenic coding variants that represented a burden at the exon level associated with the pathogenesis of PF. MethodsPF case cohorts included the PROFILE study of incident idiopathic pulmonary fibrosis (IPF) and PF-classified participants from the Genomics England 100K (GE100KGP) study. Whole genome sequencing data were used to test the burden of rare protein altering variants (PAVs; CADD score >20) defined by minor allele frequency <0.1% in the summary level gnomAD reference database (v3.1.2). A summary exon-level pathogenicity score was derived by standardising PAV predictions from functional annotation tools (AlphaMissense, REVEL, ClinPred, CADD, PolyPhen-2, SIFT) averaged across exons. SKAT-O based kernel regression associated exon-level pathogenicity features with disease progression and survival. Single cell lung transcriptomic datasets were harmonised to evaluate expression patterns and gene ontology characterised enriched molecular functions. ResultsAcross 507 PROFILE cases and 451 GE100KGP cases, each compared against 76,156 reference participants, 77 genes showed overlapping significant rare PAV burden, comprising 206 concordant PAVs. Of these, 15 genes had exons with pathogenicity scores that were associated with worse clinical outcomes in IPF, including FAT4 exon-10 and DNAH7 exon-43. Dysregulated gene expression of COL6A3 and FAT4 was observed in IPF lung fibroblasts, while DNAH7, DNAH12 and PCM1 showed high expression in IPF epithelial cells. The top enriched molecular functions were related to cytoskeletal motor activity. ConclusionsRare PAV burden highlighted that pathogenicity within specific exons was associated with PF risk and worse clinical outcomes, identifying genes with dysregulated expression in disease lung cells. The genetic architecture implicates disrupted cytoskeletal organisation in the pathogenesis of PF.

genetics↗

bioRxiv2024

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated. MethodsWe adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length. ResultsThe genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. ConclusionOur study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

genomics↗

bioRxiv2022

Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis

Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry-based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

cell biology↗

bioRxiv2020

Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis

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, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. 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 (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.

immunology↗

bioRxiv2020

Identification of a novel missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite significant progress, the genetic determinants of this disease remain incompletely defined. Using next generation sequencing data from 752 individuals with sporadic IPF and 119,055 controls, we performed both variant- and gene-level analyses to identify novel IPF genetic risk factors. Our variant-level analysis revealed a novel rare missense variant in SPDL1 (NM_017785.5 p.Arg20Gln; p = 2.4 x 10-7, odds ratio = 2.87). This signal was independently replicated in the FinnGen cohort (combined p = 2.2 x 10-20), firmly associating this variant as a novel IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. Our results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

genetics↗

bioRxiv2018

Longitudinal prediction of outcome in idiopathic pulmonary fibrosis using automated CT analysis

AIMSTo evaluate computer-derived (CALIPER) CT variables against FVC change as potential drug trials endpoints in IPF.\n\nMETHODS71 Royal Brompton Hospital (discovery cohort) and 23 Mayo Clinic Rochester and 24 St Antonius Hospital Nieuwegein IPF patients (validation cohort) were analysed. Patients had two CTs performed 5-30 months apart, concurrent FVC measurements and were not exposed to antifibrotics (to avoid confounding of mortality relationships from antifibrotic use). Cox regression analyses (adjusted for patient age and gender) evaluated outcome for annualized FVC and CALIPER vessel-related structures (VRS) change and examined the added prognostic value of thresholded VRS changes beyond standard FVC change thresholds.\n\nRESULTSChange in VRS was a stronger outcome predictor than FVC decline when examined as continuous variables, in discovery and validation cohorts. When FVC decline ([≥]10%) and VRS thresholds were examined together, the majority of VRS change thresholds independently predicted outcome, with no decrease in model fit. When analysed as co-endpoints, a VRS threshold of [≥]0{middle dot}40 identified 30% more patients reaching an endpoint than a [≥]10% FVC decline threshold alone.\n\nCONCLUSIONSChange in VRS is a strong predictor of outcome in IPF and can increase power in future drug trials when used as a co-endpoint alongside FVC change.\n\nEthics committee approvalApproval for this study of clinically indicated CT and pulmonary function data was obtained from Liverpool Research Ethics Committee (Reference: 14/NW/0028) and the Institutional Ethics Committee of the Royal Brompton Hospital, Mayo Clinic Rochester and St. Antonius Hospital, Nieuwegein. Informed patient consent was not required.\n\nTake home messageChange in the vessel-related structures, a computer-derived CT variable, is a strong predictor of outcome in idiopathic pulmonary fibrosis and can increase power in future drug trials when used as a co-endpoint alongside forced vital capacity change.

bioinformatics↗

bioRxiv2018

Patient reported distress can aid clinical decision making in idiopathic pulmonary fibrosis: analysis of the PROFILE cohort

Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease. We aimed to determine if patient response to a palliative assessment survey could predict disease progression or death. We undertook a cross-sectional study in a UK clinical cohort of incident cases. Rasch-based methodology provided a disease distress value from an abridged 11 item model of the original 45 item survey. Distress values were compared with measures of lung function. Disease progression or mortality alone was predicted at twelve months from survey completion, with risk of death assessed at three, six and twelve months. Disease distress values were negatively correlated with lung function (r=-0.275 percent predicted DLCO). Expected survey scores computed from distress values could distinguish disease progression, 8.8 (p=0.004), and people who died, 10.2 (p=0.002), from those who did not progress, 6.9. Actual survey scores predicted disease progression and mortality with an area under the curve of 0.60 and 0.64, respectively. Each point increment in actual score increased risk of twelve-month mortality by 10%, almost 43% of people scoring above 18 did not survive beyond 105 days. We define a short questionnaire that can score disease distress and predict prognosis, assisting clinical decision making in progressive fibrosis.

clinical trials↗