Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.

An explorative metabolomic analysis of the endothelium in pulmonary hypertension

“…Our observations are in alignment with those of Kariotis and colleagues, who identified three whole-blood transcriptomic patient subgroups of IPAH patients that accounted for more than 90% of the cohorts 22 . These subgroups were associated with poor, moderate, and good prognoses.. Our study also extends to CTEPH patients, suggesting that the metabolic phenotypes are not restricted to PAH.…”

Inflammasome Activation in Pulmonary Arterial Hypertension

“…Important work remains in characterizing biomarkers of inflammasome activation in patients with PAH arising from diverse causes. Several such efforts are underway currently, and have reported novel potential groupings of PAH patients based on sequencing efforts ( 59 , 60 ). Once a systematic assessment has been made, clinical trials can begin in targeted populations most likely to derive benefit from these translational therapies.…”

NCAPG Promotes Pulmonary Artery Smooth Muscle Cell Proliferation as a Promising Therapeutic Target of Idiopathic Pulmonary Hypertension: Bioinformatics Analysis and Experiment Verification

“…Some PAH gene mutations, such as the gene encoding bone morphogenetic protein type 2 receptor (BMPR2) protein, have been identified by whole-genome sequencing [ 17 ]. A recent study showed that unsupervised machine learning analysis of the whole blood transcriptome of IPAH patients could divide 92% of IPAH patients into three subgroups, each with unique whole blood transcriptomic and clinical features associated with prognosis [ 18 ]. These studies may indicate genetic differences in PAH.…”