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.
Key Findings
Methods
Targeted sequencing of PH-related genes was performed in 152 patients across three groups, with COPD and ILD patients stratified by PH severity on right heart catheterisation.
The cohort comprised 63 patients with COPD, 51 with ILD, and 38 with idiopathic pulmonary arterial hypertension (IPAH).
COPD and ILD patients were stratified according to PH severity assessed by right heart catheterisation.
The study aimed to investigate the contribution of genetic factors to PH development and severity in chronic lung disease.
Results
Patients with ILD-associated PH carried fewer genetic variants than ILD patients without PH, whereas COPD-associated PH showed the opposite trend.
The abstract describes this as an 'opposite trend' in COPD-PH relative to ILD-PH.
This pattern supports a stronger genetic contribution to PH in COPD than in ILD.
Results
Variants of uncertain significance (VUS) in PAH-associated genes were found in a small subset of COPD-PH and ILD-PH patients.
VUS in BMPR2 and BMPR1B were identified in two of 28 patients with severe COPD-PH.
A VUS in SMAD9 was identified in one patient with nonsevere ILD-PH.
Results
VUS in extracellular matrix-related genes were identified in patients with severe COPD-PH.
VUS in THBS1 and LOXL2 were found in four patients with severe COPD-PH.
These genes are involved in vascular remodelling.
Results
VUS in an inflammation-related gene (TNFAIP6) were identified in two patients with ILD-PH.
TNFAIP6 is described as an inflammatory-related gene.
This differs from the extracellular matrix and PAH-gene VUS seen in severe COPD-PH.
Results
Pathogenic/likely pathogenic variants in PAH-associated genes were found exclusively in IPAH patients, not in COPD-PH or ILD-PH.
Among COPD and ILD patients, only VUS (not pathogenic/likely pathogenic variants) were found in PAH-associated genes.
The IPAH group (n=38) served as the comparison population.
Conclusions
The authors conclude that genetic overlap between COPD-PH and ILD-PH is limited, with a stronger genetic contribution in COPD, especially severe COPD-PH.
A subset of severe COPD-PH patients carries VUS in PAH-associated genes or genes involved in vascular remodelling.
The distinct rare-variant profiles suggest different genetic underpinnings of PH in the two lung diseases.
What This Means
This study looked at whether inherited genetic differences might help explain why some people with chronic lung diseases, such as COPD or interstitial lung disease (ILD), develop pulmonary hypertension (high blood pressure in the lung arteries), and why it is more severe in some. Researchers sequenced a panel of PH-related genes in 63 people with COPD, 51 with ILD, and 38 with idiopathic pulmonary arterial hypertension (IPAH), and grouped the lung disease patients by how severe their PH was on heart catheter measurements.
They found that ILD patients with PH had fewer genetic variants than ILD patients without PH, while COPD patients with PH showed the opposite trend. A small number of patients with severe COPD-PH carried variants of uncertain significance in genes linked to pulmonary arterial hypertension (BMPR2, BMPR1B) or in genes involved in tissue remodelling (THBS1, LOXL2). A few ILD-PH patients had variants in genes related to inflammation (TNFAIP6) or SMAD9. Clearly disease-causing variants in PAH genes were found only in the IPAH group.
This research suggests that genetics may play a larger role in PH in COPD, particularly severe cases, than in ILD, and that the two conditions have little genetic overlap. Most of the variants were of uncertain significance and found in few patients, so their actual effects are unclear and the findings do not yet point to clinical use.
Bosacoma A, Garcia A, Madrigal I, Lozano J, Sidorova J, Aguilar D, et al.. (2026). Targeted DNA Sequencing Reveals Distinct Rare-Variant Profiles in Pulmonary Hypertension Associated with Chronic Lung Diseases.. International journal of molecular sciences. https://doi.org/10.3390/ijms27208992