ArticleAmerican journal of respiratory and critical care medicine2014
Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension.
Article in American journal of respiratory and critical care medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03251872 (Olaparib for Pulmonary Arterial Hypertension), which is not on this map. Cited by 57 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Olaparib for Pulmonary Arterial Hypertension: a Pilot Clinical Study
Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- A systematic review of genetic mutations in pulmonary arterial hypertension.BMC medical genetics · 2017Pooled it
- Molecular-Genetic Basis of Pulmonary Arterial Hypertension (PAH).Current issues in molecular biology · 2026Review
- Proangiogenic effect and molecular mechanism of a new cytosporin derivative from the marine fungus Eutypella sp. D-1.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Novel insights into the potential applications of stem cells in pulmonary hypertension therapy.Respiratory research · 2024Review
- Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.International journal of molecular sciences · 2024Article
- Exploring the pathogenesis of pulmonary vascular disease.Frontiers in medicine · 2024Review
- Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension.Nature communications · 2023Article
- Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function.Vascular pharmacology · 2023Article
- Wnt7a deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension.The European respiratory journal · 2023Article
- Endothelial Senescence: A New Age in Pulmonary Hypertension.Circulation research · 2022Review
- Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan.Frontiers in cardiovascular medicine · 2022Article
- Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus.Cardiovascular research · 2021Review
- Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.The Journal of clinical investigation · 2021Article
- In Defense of the Nucleus: NUDT1 and Oxidative DNA Damage in Pulmonary Arterial Hypertension.American journal of respiratory and critical care medicine · 2021Article
- NovelFrontiers in medicine · 2021Article
- Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases.Frontiers in cell and developmental biology · 2021Article
- Peroxisome proliferator-activated receptor agonists and reversal of vascular degeneration through DNA repair, a step toward drug-induced regenerative medicine.Cardiovascular endocrinology & metabolism · 2020Review
- 'There and Back Again'-Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension.Genes · 2020Review
- Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension.Journal of the American Heart Association · 2020Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 2 countries.
Funding
Abstract
rationaleIdiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and ∼15% of patients with IPAH, their low penetrance (∼20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown.
objectivesTo determine whether WES can help identify novel gene modifiers in patients with IPAH.
methodsExome capture and sequencing was performed on genomic DNA isolated from 12 unrelated patients with IPAH lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR. MEASUREMENTS AND MAIN
resultsA total of nine genes were identified as high-priority candidates. Our top hit was topoisomerase DNA binding II binding protein 1 (TopBP1), a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from patients with IPAH. Although TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival.
conclusionsWES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.