Characterisation of a COPD-associated nephronectin (NPNT) functional splicing genetic variant in human lung tissuevialong-read sequencing
Year: 2025
Type: article
Abstract: Background Identification of COPD disease-causing genes is an important tool for understanding why COPD develops, who is at highest COPD risk and how new COPD treatments can be developed. Previous COPD genetic studies have identified a highly significant genetic association nearNPNT(nephronectin), a gene involved in tissue repair, but the biological mechanisms underlying this association are unknown. Methods Splicing quantitative trait locus (sQTL) analysis was performed to identify common genetic variants that alter RNA splicing in lung tissues. These lung sQTL signals were compared to COPD genetic association results near theNPNTgene using colocalisation analysis to determine whether genetic risk for COPD in this region may act through altered splicing. Long-read sequencing characterised COPD-associated splicing events at isoform-level resolution andin silicoprotein structural analysis identified likely functional effects of this alternative splicing. Results An established COPD genetic risk variant, rs34712979-A, creates a cryptic splice acceptor site that causes four separate splicing changes inNPNT. The only one of these splicing changes that was associated with COPD phenotypes involved a cassette exon (exon 3). Long-read RNA sequencing demonstrated that the COPD risk allele causes a shift in isoform usage away from the dominantNPNTisoform B precursor, which excludes exon 3, to the isoform A precursor, which splices-in exon 3. AlphaFold protein structural analysis reveals that inclusion of this exon disrupts an epidermal growth factor-like functional domain in NPNT. Conclusion Genetic variants in theNPNTgene increase COPD risk by changing RNA splicing ofNPNTin the lung.
Source: European Respiratory Journal
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Center for Tobacco Products, Common Fund
Awards: Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, G264675175, G2816736420, INTEGRATIVE GENOMICS OF CLINICAL SUBTYPES IN COPDGENE, G3194560040, G3256118428, Prospective Health Outcomes and Inflammatory Biomarkers Associated with e-Cigarette Use, G4030405119, Rare variants and NHLBI traits in deeply phenotyped cohorts, G5258357286, (2 of 2) Genetic Epidemiology of COPD, Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL, (1 of 2) Genetic Epidemiology of COPD, SYSTEMS GENOMICS OF THE ASTHMA-COPD OVERLAP SYNDROME, Integrative genomic, transcriptomic and proteomic studies of pulmonary function and COPD, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G8354759825, G8997417011, G9000091268, G9000228787, COPD GWAS Functional Variant Identification in Airway Epithelial Cells using Deep Learning Splicing Models, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers, Integrative 'Omics of Transcriptome Complexity in COPD, Variant induced RNA structure change in human genetic disease, Non-coding RNA structure change in Chronic Obstructive Pulmonary Disease, UNC Cystic Fibrosis Research and Translation Core Center
OpenAlex ID: W4407768533