C18-07 Genetic Determinants of Pulmonary Artery Enlargement in Over 50,000 Subjects With and Without COPD

Abstract Rationale The pulmonary artery (PA) diameter, readily measurable on chest CT or MRI, is an established predictor of adverse outcomes in pulmonary hypertension and in COPD. However, the genetic determinants of PA enlargement remain incompletely characterized. In this study, we performed a comprehensive genomic analysis in both COPD-enriched and population-based cohorts to identify common and rare variants associated with PA size. Methods We first conducted genome-wide association analyses of common variants (MAF0.01) and gene-based tests of rare missense and loss-of-function variants for PA diameter and PA-to-aorta ratio (PA/A) using regenie in the COPD-enriched COPDGene and ECLIPSE studies. Models were adjusted for cohort, age, sex, FEV1, BMI, smoking pack-years, and genetic ancestry. PA diameter was analyzed as a continuous trait, while PA/A was analyzed both as continuous and binary outcome (1 vs. ≤1). We also performed a meta-analysis across COPDGene, ECLIPSE, and UK Biobank, followed by replication in the Framingham Heart Study (FHS). Genomic risk loci were defined by grouping genome-wide significant variants with strong LD (r²≥0.6) within a 250-kb window. A secondary clumping at r²≥0.1 was then performed to identify lead SNPs representing each locus. Functional follow-up included tissue-specific expression profiling, gene set enrichment, and single-cell annotation analyses using the FUMA platform. Genome-wide significance was set at P 5 × 10⁻8, exome-wide significance at gene-based Bonferroni correction, and enrichment analyses at FDR0.05. Results In analyses of COPDGene (n = 10,198) and ECLIPSE (n = 1,859), we identified genome-wide significant loci near ANO1 associated with PA diameter, and near ACYP2 and SHBP4 associated with PA/A. In the rare variant exome analyses, variants in ARIH2 were associated with PA enlargement (PA/A1) in all participants (P 2.7x10⁻6), and PMFBP1 variants with continuous PA/A in COPD GOLD2 cases (P 1.4x10-6). Meta-analysis of COPDGene, ECLIPSE, and the UK Biobank (which contributed ∼40,000 participants) identified 67 loci (P 5 × 10⁻8), of which 37 were nominally significant and directionally consistent (P 0.05) in COPDGene and ECLIPSE, and 13 represented novel signals. In FHS (n = 3,289), two of the novel loci (METTL7A and KLHL42) replicated (P 0.05), with 5 additional loci showing directional consistency. Enrichment analyses highlighted immune-mediated regulatory processes, with pericytes, smooth muscle cells, and fibroblasts showing the strongest locus-specific expression (FDR0.05). Conclusions In the largest genetic association study to date of pulmonary vascular imaging traits, we identified multiple novel loci, implicating immune regulatory pathways and cell types involved in pulmonary vascular remodeling. Genetic loci associated with PA diameter exhibit substantial overlap between population-based and COPD-enriched cohorts. This abstract is funded by: This work was supported by Max Kade Fellowship, TOPMed Fellowship, NHLBI R01 HL167072. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion. Molecular data from the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).