Renzoni, E. | Search bioRxiv

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↗

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↗