Introduction: Mechanisms underpinning pulmonary vascular disease in COPD have not yet been well-elucidated. Pulmonary artery enlargement (PAE), measured by CT as PA/A ratio of the diameter of the pulmonary artery to that of the aorta >1, correlates with pulmonary hypertension by right heart catheterization and is associated with worse clinical outcomes. Genome-wide association studies previously identified multiple associations with PAE, but these studies lacked comprehensive coverage of genetic variants and the biological functions of the associated variants are unknown. To identify novel genetic determinants for PAE and characterize the functions of PAE-associated variants, we performed a whole-genome sequencing (WGS) analysis and integrated the results with publicly available epigenomic data.
Methods: 5,131 subjects with available WGS and PA/A data in the COPDGene non-Hispanic-Whites, COPDGene African-Americans, and ECLIPSE studies were analyzed. PA/A (> or ≤ 1) was tested for genetic associations using variants with MAF>0.01% in the TOPMed Freeze8 data, and adjusting for age, sex, smoking, and genetic ancestry. Separate analyses in each population were followed by a meta-analysis. We performed single-variant, gene-based, and pathway analyses. We then quantified the enrichment of PAE-WGS regions in DNaseI peaks from ENCODE and Roadmap cell types.
Results: We identified two loci associated with PAE at genome-wide significance: One previously reported (15q31 near IREB2) and one new (12p12 near LMO3) risk loci. Additional novel loci approaching genome-wide significance included regions near FREM2, CHEK2, and ZNF516. Top signals were enriched for several cell types including BMP4-derived mesendoderm cells and fibroblasts. Gene-based and pathway analyses highlighted potentially relevant biological mechanisms, including immune response and cytoskeleton remodeling (FDR 10%).
Conclusion: This study leveraged imaging, genomics, epigenomics, and advanced bioinformatics tools and provided insights into new putative genetic determinants of pulmonary vascular remodeling in COPD. Additional analyses are needed to replicate these findings and understand their consequences on downstream processes.
Grant support: NHLBI K08HL141601, R01HL116931, R01HL124233, R01HL126596, R01HL116473, U01 HL089897 and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, and Sunovion.