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.

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 Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension

2012 ◽  
Vol 302 (6) ◽  
pp. L541-L554 ◽  
Author(s):  
James P. Maloney ◽  
Robert S. Stearman ◽  
Todd M. Bull ◽  
David W. Calabrese ◽  
Megan L. Tripp-Addison ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Cell Growth ◽  
Arterial Hypertension ◽  
Rna Splicing ◽  
Type I ◽  
Loss Of Function ◽  
Intronic Mutation ◽  
Thrombospondin 1 ◽  
Pulmonary Arterial

Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene ( BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-β and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene ( THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-β regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-β. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted.

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.

Abstract 17301: Functional Characterization of KCNK3 Mutants Associated With Pulmonary Arterial Hypertension Under Physiologically Relevant Heterozygous Conditions

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michael S Bohnen ◽  
Danilo Roman-Campos ◽  
Cecile Terrenoire ◽  
Jack Jnani ◽  
Lei Chen ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Ph Dependence ◽  
Functional Characterization ◽  
Resting Membrane Potential ◽  
Channel Activity ◽  
Loss Of Function ◽  
Pulmonary Arterial ◽  
Specific Impact

KCNK3 encodes a two-pore domain K+ channel, TASK-1, which is inhibited by extracellular acidity and hypoxia. Expressed in a variety of tissues, including human pulmonary artery smooth muscle cells (hPASMCs), the central nervous system, pancreas, and adrenal glands, TASK-1 contributes to the resting membrane potential of cells in which it is expressed. Recently, our group reported mutations in KCNK3 underlying idiopathic pulmonary arterial hypertension (PAH), resulting from loss of TASK-1 function, partially pharmacologically rescuable with ONO-RS-082. TASK-1 dimerizes in vivo, forming functional channels with another TASK-1 subunit or with the related TASK-3 channel. TASK-1 and TASK-3 often are expressed in the same cells, although it has been reported that TASK-1 alone is expressed in the lung. Our initial study examined mutant and wildtype (WT) homodimeric TASK-1 channels expressed heterologously in COS-7 cells. Here we further characterize PAH-linked TASK-1 mutations in physiologically relevant heterozygous conditions in COS-7 and hPASMC cell lines. We engineered heterodimeric channels consisting of one mutant and one WT subunit; compared this with co-expression of mutant and WT channels; and measured channel activity with whole cell patch clamp procedures. We found a mutation specific impact of heterozygosity on channel activity. One mutation, V221L, produces a shift in pH dependence accounting for loss of function at physiological pH 7.4, partially rescued by dimerization with a WT subunit, while another, G203D, produces near complete loss of function as a homo- or hetero-dimer. The presence of TASK-3 results in greater rescue of V221L TASK-1 activity at pH 7.4 than does WT TASK-1. Additionally, under current clamp we found that ONO-RS-082 hyperpolarizes the membrane potential in hPASMCs expressing WT or V221L TASK-1, reversible by selective block of TASK-1 with ML365. Together, our results suggest (a) TASK-1 mutant heterodimers exhibit loss of function with mutation specific severity; (b) TASK-3 may rescue mutant TASK-1 and underlie a tissue specific impact of the TASK-1 mutations observed clinically; and (c) PAH TASK-1 mutants can be pharmacologically modulated in hPASMCs and alter the critically important resting membrane potential.

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 Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1261
Author(s):  
Hélène Le Ribeuz ◽  
Véronique Capuano ◽  
Barbara Girerd ◽  
Marc Humbert ◽  
David Montani ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Potential ◽  
Pulmonary Vasculature ◽  
K Channel ◽  
Loss Of Function ◽  
Epigenetic Factors ◽  
Regulatory Subunits ◽  
Pulmonary Arterial ◽  
Or Task

Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic predisposition, epigenetic factors, and environmental factors (drugs, toxins, viruses, hypoxia, and inflammation), which contribute to the initiation or development of irreversible remodeling of the pulmonary vessels. The recent identification of loss-of-function mutations in KCNK3 (KCNK3 or TASK-1) and ABCC8 (SUR1), or gain-of-function mutations in ABCC9 (SUR2), as well as polymorphisms in KCNA5 (Kv1.5), which encode two potassium (K+) channels and two K+ channel regulatory subunits, has revived the interest of ion channels in PAH. This review focuses on KCNK3, SUR1, SUR2, and Kv1.5 channels in pulmonary vasculature and discusses their pathophysiological contribution to and therapeutic potential in PAH.

Transition from intravenous treprostinil to enteral selexipag in an infant with pulmonary arterial hypertension

2019 ◽  
Vol 29 (06) ◽  
pp. 849-851 ◽  
Author(s):  
Rachel Koo ◽  
Jennifer Lo ◽  
Matthew J. Bock
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Adverse Effects ◽  
Arterial Hypertension ◽  
Receptor Agonist ◽  
Ip Receptor ◽  
Pulmonary Arterial

AbstractSelexipag is an enteral, selective prostacyclin IP receptor agonist approved for pulmonary hypertension in adults. There are few reports of its use in children and none in infants. We report the first transition of an infant (11.5 months, 8.6 kg) from intravenous treprostinil (40 ng/kg/minute) to enteral selexipag (400 mcg twice daily) with a good response and no adverse effects.

scholarly journals SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Tian-Ming Wang ◽  
Shan-Shan Wang ◽  
Ying-Jia Xu ◽  
Cui-Mei Zhao ◽  
Xiao-Hui Qiao ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Loss Of Function ◽  
Pulmonary Arterial

Abstract 15092: The Yin-yang of Bmpr2 and Ces1 in the Pulmonary Endothelium Aad Its Role in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Stuti Agarwal ◽  
Ananya Chakraborty ◽  
David Condon ◽  
Salvador Tello ◽  
Karthik Suresh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Redox Balance ◽  
Tube Formation ◽  
Vascular Lesions ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Pulmonary Endothelium ◽  
Pulmonary Arterial

Background/Hypothesis: Pulmonary Arterial Hypertension (PAH) is a life-threatening disease characterized by loss of pulmonary microvessels and vascular remodeling. Loss of function BMPR2 mutations contribute to pulmonary endothelial cell (EC) apoptosis and oxidative stress, but their reduced penetrance suggests need for additional modifiers. Carboxylesterase1 (CES1) is endoplasmic reticulum (ER) enzyme responsible for detoxification, proteostasis, and redox balance. Similar to BMPR2 mutations, we found that loss of CES1 is associated with oxidative stress and apoptosis. In this study, we explore a plausible link between BMPR2 pathway and CES1 regulation in promoting EC survival and angiogenesis. Methods: PECs & lung tissue from healthy donors and PAH patients were obtained from PHBI. To induce oxidative stress, we used H 2 O 2 (100 μM) & methamphetamine HCl (METH, 0.5-2mM). Both siRNA and pharmacological approaches were used to inhibit BMPR2, Nrf2, and CES1 expression. Caspase and Matrigel assays were used to assess PEC survival and tube formation, respectively. Results: RNAseq of BMPR2-mutant PECs showed significantly less CES1 expression, which correlated with reduced protein expression in PEC lysates and within lung vascular lesions. In healthy PECs, BMP9 stimulation led to increase in CES1 expression that was absent post BMPR2 knockdown. CES1 gene transcription was by BMPR2-dependent activation of Nrf2, a transcription factor responsible for antioxidant gene expression and mitochondrial biogenesis. Inhibition of Nrf2 activation by ML385 (5μM) abrogates BMP9 induced CES1 mRNA levels similar to BMPR2 knockdown. The connection between BMPR2 and CES1 was further strengthened by CES1 knockdown studies in PECs that demonstrated reduction in BMPR2 protein synthesis associated with ER stress and reduced autophagy. Finally, lung examination in CRISPR generated CES1 +/- mice demonstrated increased microvascular muscularization at normoxia compared to wild type mice. Conclusion: BMPR2 and CES1 are part of common signaling pathway that protects PECs against oxidative stress and mitochondrial damage through a positive feedback loop. Interventions that restore CES1 activity could rescue BMPR2 signaling and serve as novel PAH therapeutics.

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