Genetic variants in pulmonary hypertension associated with chronic obstructive pulmonary disease

To synthesize emerging evidence supporting genetic susceptibility to pulmonary vascular phenotypes in chronic obstructive pulmonary disease (COPD) and to provide a rationale for focused genomic investigation of pulmonary hypertension associated with COPD (PH-COPD).

Multiancestry genome-wide association studies and integrative genomic analyses have identified COPD risk loci involved in pathways related to lung development, extracellular matrix remodeling, angiogenesis, immune signaling, and hypoxia responses, processes that intersect with pulmonary vascular biology. Concurrent advances in pulmonary arterial hypertension (PAH) genetics demonstrate that rare pathogenic variants in developmental and endothelial signaling genes produce vascular phenotypes often accompanied by reduced diffusing capacity, parenchymal abnormalities, and proliferative vasculopathy. Consistent with these observations, data from independent PAH cohorts reveal phenotypic overlap and biological heterogeneity between group 1 and group 3 classifications. Collectively, these findings suggest that a subset of COPD patients with pulmonary hypertension may harbor unrecognized genetic susceptibility influencing pulmonary vascular remodeling. However, dedicated genetic studies specifically examining PH-COPD remain limited.

PH-COPD may represent, in part, a genetically influenced disease that extends beyond the traditional PH group boundaries. Systematic genomic sequencing coupled with clinical, imaging, and physiological phenotyping will be essential to identify biologically defined subgroups and guide precision therapeutic strategies.