Targeted DNA Sequencing Reveals Distinct Rare-Variant Profiles in Pulmonary Hypertension Associated with Chronic Lung Diseases

Abstract

The mechanisms underlying the development and severity of pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) remain poorly understood. To investigate the contribution of genetic factors, we performed targeted sequencing of PH-related genes in 63 patients with COPD, 51 with ILD, and 38 with idiopathic pulmonary arterial hypertension (IPAH), stratifying COPD and ILD patients according to PH severity, assessed by right heart catheterisation. Patients with ILD-associated PH harboured fewer genetic variants than those without PH, whereas an opposite trend was observed in COPD-associated PH. Variants of uncertain significance (VUS) in PAH-associated genes (BMPR2, BMPR1B) were identified in two out of 28 patients with severe COPD-PH and in one with nonsevere ILD-PH (SMAD9). VUS in extracellular matrix-related genes (THBS1, LOXL2) were also identified in four patients with severe COPD-PH, and in inflammatory-related genes (TNFAIP6) in two patients with ILD-PH. Pathogenic/likely pathogenic variants in PAH-associated genes were exclusive to IPAH. We conclude that there is limited genetic overlap between COPD-PH and ILD-PH, with a stronger genetic contribution to PH in COPD, particularly in its severe form, where a subset of patients carries VUS in PAH-associated genes or genes involved in vascular remodelling.