scholarly journals Common genetic variants in pulmonary arterial hypertension

2019 ◽  
Vol 7 (3) ◽  
pp. 190-191 ◽  
Author(s):  
Sue Gu ◽  
Rahul Kumar ◽  
Michael H Lee ◽  
Claudia Mickael ◽  
Brian B Graham
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

scholarly journals Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 638
Author(s):  
Shahood Fazal ◽  
Malik Bisserier ◽  
Lahouaria Hadri
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Genetic Variants ◽  
High Throughput Sequencing ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.

scholarly journals Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension

2018 ◽  
Vol 6 (5) ◽  
pp. 835-844
Author(s):  
Yeganeh Abbasi ◽  
Javad Jabbari ◽  
Reza Jabbari ◽  
Charlotte Glinge ◽  
Seyed Bahador Izadyar ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Exome Data ◽  
Pulmonary Arterial

scholarly journals Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Shaun Pienkos ◽  
Natalia Gallego ◽  
David F. Condon ◽  
Alejandro Cruz-Utrilla ◽  
Nuria Ochoa ◽  
...  
Keyword(s):  
Immune Response ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Vascular Remodeling ◽  
Biliary Cirrhosis ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
The Impact ◽  
Healthy Lung

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH.Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting.Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h.Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

Genetic variants in a Polish population of patients with pulmonary arterial hypertension: sequencing of BMPR2, ALK1, and ENG genes

2018 ◽  
pp. 852-859 ◽  
Author(s):  
Barbara Uznańska-Loch ◽  
Kamil Wikło ◽  
Dominika Kulczycka-Wojdala ◽  
Bożena Szymańska ◽  
Łukasz Chrzanowski ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Polish Population ◽  
Pulmonary Arterial

scholarly journals Pulmonary arterial hypertension-associated genetic variants in combined post-capillary and pre-capillary pulmonary hypertension: a case report

2021 ◽  
Vol 11 (1) ◽  
pp. 204589402199657
Author(s):  
Chomette L ◽  
Caravita S ◽  
Dewachter C ◽  
Abramowicz M ◽  
Vachiery JL ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Heart Disease ◽  
Case Report ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Cardiac Transplantation ◽  
Predisposing Factors ◽  
Left Heart ◽  
Pulmonary Arterial

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.

scholarly journals A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension

2021 ◽  
Vol 15 ◽  
pp. 175346662110136
Author(s):  
James C. Coons ◽  
Karryn Crisamore ◽  
Solomon Adams ◽  
Ashley Modany ◽  
Marc A. Simon ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Adverse Effects ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Treatment Discontinuation ◽  
Activity Score ◽  
Loss Of Function ◽  
Treatment Persistence ◽  
Pulmonary Arterial ◽  
Cyp2c9 Activity

Background and aims: Treprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing. Methods: Patients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher’s exact test was used for categorical data and Kruskal–Wallis test or Wilcoxon rank sum were used for continuous data. Results: A total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing. Conclusion: Genetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor. The reviews of this paper are available via the supplemental material section.

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