Common genetic variants in pulmonary arterial hypertension.
Ontology highlight
ABSTRACT:
SUBMITTER: Gu S
PROVIDER: S-EPMC6768546 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Common genetic variants in pulmonary arterial hypertension.
Gu Sue S Kumar Rahul R Lee Michael H MH Mickael Claudia C Graham Brian B BB
The Lancet. Respiratory medicine 20181205 3
Similar Datasets
Project description:BackgroundWe aimed to provide a set of previously reported PAH-associated missense and nonsense variants, and evaluate the pathogenicity of those variants.MethodsThe Human Gene Mutation Database, PubMed, and Google Scholar were searched for previously reported PAH-associated genes and variants. Thereafter, both exome sequencing project and exome aggregation consortium as background population searched for previously reported PAH-associated missense and nonsense variants. The pathogenicity of previously reported PAH-associated missense variants evaluated by using four in silico prediction tools.ResultsIn total, 14 PAH-associated genes and 180 missense and nonsense variants were gathered. The BMPR2, the most frequent reported gene, encompasses 135 of 180 missense and nonsense variants. The exome sequencing project comprised 9, and the exome aggregation consortium counted 25 of 180 PAH-associated missense and nonsense variants. The TOPBP1 and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis.ConclusionThis is the first evaluation of previously reported PAH-associated missense and nonsense variants. The BMPR2 identified as the major gene out of 14 PAH-associated genes. Based on findings, the ENG and TOPBP1 gene are not likely to be the monogenic cause of PAH.
| S-EPMC6160702 | biostudies-literature
Project description:Predisposing factors for the development of a pre-capillary component in pulmonary hypertension associated with left heart disease remain elusive. We report the case of a patient with persistent combined post-capillary and pre-capillary pulmonary hypertension after cardiac transplantation, in whom a rare BMPR2 variant was found.
| S-EPMC7934041 | biostudies-literature
Project description:BackgroundAnimal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A(1c) (HbA(1c)) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for DM. We aimed to define the prevalence of elevated HbA(1c) in PAH patients and to correlate HbA(1c) levels with functional assessment.MethodsHbA(1c) was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA(1c) ≤ 5.9% defined normal, 6.0% to 6.4% was glucose intolerance, and ≥ 6.5% was DM.ResultsTwenty-three patients (56%) had HbA(1c) ≥ 6.0%, and 6 (15%) had unrecognized DM (HbA(1c) ≥ 6.5%). Age and body mass index were similar in patients with HbA(1c) ≥ 6.0% vs < 6.0%. There was a trend towards lower mean 6-minute walk distance in patients with elevated HbA(1c) (331.0 ± 126.6 vs 413.6 ± 74.9 meters, p = 0.07). The 6-month event-free survival was not significantly different in patients with elevated HbA(1c).ConclusionsUnrecognized glucose intolerance as assessed by HbA(1c) is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.
| S-EPMC3129440 | biostudies-literature
Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other
2003-11-15 | GSE703 | GEO
Project description:BackgroundPulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown.Methods40 patients with SAPH were individually matched to 40 sarcoidosis patients without PH (SA). Whole exome sequencing was performed to identify rare genetic variants in a diagnostic PH gene panel of 13 genes. Additionally, an exploratory analysis was performed to search for other genes of interest. From 572 genes biologically involved in PH pathways, genes were selected in which at least 15% of the SAPH patients and no more than 5% of patients without PH carried a rare variant.ResultsIn the diagnostic PH gene panel, 20 different rare variants, of which 18 cause an amino-acid substitution, were detected in 23 patients: 14 SAPH patients carried a variant, as compared to 5 SA patients without PH (p = 0.018). Most variants were of yet unknown significance. The exploratory approach yielded five genes of interest. First, the NOTCH3 gene that was previously linked to PH, and furthermore PDE6B, GUCY2F, COL5A1, and MMP21.ConclusionsThe increased frequency of variants in PH genes in SAPH suggests a mechanism whereby the presence of such a genetic variant in a patient may increase risk for the development of PH in the context of pulmonary sarcoidosis. Replication and studies into the functionality of the variants are required for further understanding the pathogenesis of SAPH.
| S-EPMC9601358 | biostudies-literature
Project description:Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH.
| S-EPMC4154073 | biostudies-literature
Project description:Considering the predominant role of rare variants of the Bone morphogenetic protein 9 (BMP9) gene in the occurrence of idiopathic pulmonary arterial hypertension (IPAH), here we conducted a case-control study, together with functional validation, to explore the relationships between variants of the BMP9 gene and development of IPAH. We found minor alleles of rs3740297 (OR: 0.72, 95% CI: 0.59-0.87, P=7.77×10-5) and rs7923671 (OR: 0.76, 95% CI: 0.62-0.93, P=0.009) were significantly associated with decreased risk of IPAH. Minor alleles of rs3740297 and rs7923671 were significantly associated with increased plasma level of BMP9 in both IPAH cases and controls (P<0.001). An allele of rs7923671 showed higher relative luciferase activity compared to that containing G allele (P<0.001). Mechanism exploration found that pulmonary artery smooth muscle cells (PASMC) cell line transfected with rs3740297 C allele construct, miR-149 mimic, and antagomir miR-149 showed more sensitive change of the relative luciferase activity and BMP9 expression. This means minor allele T of rs3740297 could significantly decrease susceptibility of IPAH in Chinese population, possibly by increasing BMP9 expression through losing a miR-149 binding site. Our study provides evidence for genetic associations between two specific variants in the BMP9 gene and plasma level of BMP9, occurrence of IPAH.
| S-EPMC7041772 | biostudies-literature
Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.
2014-11-14 | E-GEOD-53408 | biostudies-arrayexpress
Project description:Arterial pulmonary hypertension is a rare disease, with little knowledge regarding its etiology, and high mortality. Development of right and later on also left ventricular heart insufficiency, secondary to pulmonary hypertension, is a negative predictive factor. Genetic and molecular processes underlying left heart ventricle remodeling over the course of pulmonary hypertension remain unknown. In particular, there is no knowledge regarding the mechanisms of left heart ventricle atrophy which was completely avoided by researchers until recently.The aim of this study was to assess changes in protein abundance in left and right heart ventricle free wall of rats in monocrotaline model of PAH.
2020-09-07 | PXD015896 | Pride
Project description:Pulmonary arterial hypertension (PAH) is a group of vascular diseases that produce right ventricular dysfunction, heart failure syndrome, and death. Although the majority of patients appear idiopathic, accumulated research work combined with current sequencing technology show that many gene variants could be an important component of the disease. However, current guidelines, clinical practices, and available gene panels focus the diagnosis of PAH on a relatively low number of genes and variants associated with the bone morphogenic proteins and transforming Growth Factor-β pathways, such as the BMPR2, ACVRL1, CAV1, ENG, and SMAD9.To provide an expanded view of the genes and variants associated with PAH, we performed a systematic literature review. Facilitated by a web tool, we classified, curated, and annotated most of the genes and PubMed abstracts related to PAH, in which many of the mutations and variants were not annotated in public databases such as ClinVar from NCBI. The gene list generated was compared with other available tests.Our results reveal that there is genetic evidence for at least 30 genes, of which 21 genes shown specific mutations. Most of the genes are not covered by current available genetic panels. Many of these variants were not annotated in the ClinVar database and a mapping of these mutations suggest that next generation sequencing is needed to cover all mutations found in PAH or related diseases. A pathway analysis of these genes indicated that, in addition to the BMP and TGFβ pathways, there was connections with the nitric oxide, prostaglandin, and calcium homeostasis signalling, which may be important components in PAH.Our systematic review proposes an expanded gene panel for more accurate characterization of the genetic incidence and risk in PAH. Their usage would increase the knowledge of PAH in terms of genetic counseling, early diagnosis, and potential prognosis of the disease.
| S-EPMC5541665 | biostudies-other