{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:06:15Z","timestamp":1780459575651,"version":"3.54.1"},"reference-count":114,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) is a progressive, fatal disease of the pulmonary vasculature characterized by obliterative remodeling of small pulmonary arteries, leading to sustained elevation of pulmonary vascular resistance, right ventricular failure, and premature death. The diagnostic gold standard remains right heart catheterization, requiring a mean pulmonary artery pressure greater than 20 mmHg at rest, a pulmonary arterial wedge pressure of 15 mmHg or below, and a pulmonary vascular resistance exceeding 2 Wood units. PAH is an autosomal dominant disorder with markedly incomplete penetrance of approximately 20\u201330%, indicating that germline mutations alone are insufficient to cause disease. Disease manifestation requires additional \u201csecond hits\u201d, including chronic hypoxia, systemic inflammation, hemodynamic stress, hormonal influences, and common genetic modifiers such as single-nucleotide polymorphisms (SNPs). This genetic and environmental complexity underpins the broad clinical heterogeneity observed across PAH subtypes, which include idiopathic PAH, heritable PAH, and disease associated with connective tissue disorders, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure. This review provides a comprehensive and critical appraisal of the molecular-genetic architecture of PAH. Thirty genes have now been implicated in disease pathogenesis, spanning seven functional categories: receptors of the TGF-\u03b2\/BMP signaling family (BMPR2, ACVRL1, ENG, BMPR1B); circulating BMP ligands (GDF2, BMP10); transcription factors (TBX4, SOX17, KLF4, FOXF1, SMAD1, SMAD4, SMAD9); membrane and polyamine transporters (ATP13A3, AQP1); potassium channel regulators (KCNA5, KCNK3, ABCC8); metabolic and mitochondrial genes (EIF2AK4, NFU1, GGCX); signaling receptors and structural proteins (NOTCH3, KDR, CAV1, PLEKHH2); vasoactive and extracellular matrix regulators (KLK1, CBLN2, CD248); and epigenetic regulators (TET2, TOPBP1). Among these, BMPR2 is the dominant contributor, accounting for 53\u201386% of heritable PAH and 14\u201335% of idiopathic cases. The remaining genes each account for fewer than 5% of cases individually, collectively reflecting a broad landscape of rare and ultra-rare genetic contributions. For each gene, we critically evaluate the strength of genetic evidence, pathogenic mechanisms, degree of mechanistic resolution, and clinical relevance. We further discuss the contribution of emerging technologies, including whole-genome sequencing, single-cell and spatial transcriptomics, multi-omics integration, iPSC-derived vascular models, and artificial intelligence, to expanding the PAH genetic architecture beyond single-gene discovery. A key theme across this landscape is convergence: despite mechanistic diversity at the gene level, most PAH-associated variants ultimately impair endothelial quiescence, promote smooth muscle proliferation, and drive apoptosis resistance through disruption of BMP signaling amplitude, transcriptional stability, ion channel homeostasis, metabolic integrity, or epigenetic regulation. This convergence supports both a unified therapeutic rationale and a precision medicine framework for genotype-stratified intervention in PAH.<\/jats:p>","DOI":"10.3390\/cimb48060572","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:37:26Z","timestamp":1780454246000},"page":"572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular-Genetic Basis of Pulmonary Arterial Hypertension (PAH)"],"prefix":"10.3390","volume":"48","author":[{"given":"Mark","family":"Okot","sequence":"first","affiliation":[{"name":"Translational Medicine Laboratory, School of Pharmacy, Optometry and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK"},{"name":"Kabarole District Local Government, Boma, Fort Portal P.O. Box 38, Uganda"},{"name":"Conservation Through Public Health, Plot 3 Mapeera Lane, Uringi Crescent, Entebbe P.O. Box 75298, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesa","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Translational Medicine Laboratory, School of Pharmacy, Optometry and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin W.","family":"Wright","sequence":"additional","affiliation":[{"name":"Translational Medicine Laboratory, School of Pharmacy, Optometry and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1968-5663","authenticated-orcid":false,"given":"Md Talat","family":"Nasim","sequence":"additional","affiliation":[{"name":"Translational Medicine Laboratory, School of Pharmacy, Optometry and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK"},{"name":"Institute of Health and Social Care, University of Bradford, Bradford BD7 1DP, UK"},{"name":"Centre for Health Agricultural and Socio-Economic Advancements (CHASA), Lalmonirhat 5500, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17534666251342898","DOI":"10.1177\/17534666251342898","article-title":"Treatment of pulmonary hypertension after seven world symposia","volume":"19","author":"Estrada","year":"2025","journal-title":"Ther. 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