Genetics Of Pulmonary Hypertension Research Articles

PH Roundtable: Genetics and Pulmonary Hypertension

PH Roundtable: Genetics and Pulmonary Hypertension

Guest Editor's Memo: Genetics Moves To Center Stage

Our understanding of pulmonary hypertension (PH) has advanced steadily. Almost 100 years ago, light microscopy provided the earliest insights into a rare progressive and fatal disease, primary pulmonary hypertension (“PPH”). Pathologists described the histopathology of PPH, with terms like “plexogenic” and “microthromboembolic” PPH. Pathologists, who specialized in pulmonary vascular disease, identified two rare disorders, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH), that mimicked PPH clinically, but were distinctly different under the microscope.By the middle of the 20th century, the introduction of pulmonary artery catheterization to the study of cardiovascular diseases produced a new level of understanding of PH based upon physiologic observations of intravascular pressures and flows, with an emphasis on mechanisms that caused constriction and relaxation of pulmonary arterioles. This era supported early efforts to treat sporadic PPH and familial PPH, now known as idiopathic and heritable pulmonary arterial hypertension (PAH) with vasodilators, eventually leading to treatments which targeted three pathways integral to vasoconstriction and vasodilation of pulmonary arterioles.Even as pathologic, physiologic, and treatment studies proceeded during the second half of the 20th century, the genetic era began. Investigators took advantage of scientific advances in genetics to discover heritable causes of PH. The first breakthrough occurred in 2000, when two research teams independently reported that mutations in the gene (BMPR2), encoding the bone morphogenetic protein type 2 receptor, caused familial PPH. Over the next two decades investigators linked DNA sequence variations in 16 additional genes to heritable forms of PAH, including PVOD and PCH. These discoveries shaped a new understanding of PAH.Investigators quickly determined that BMPR2 regulated the proliferation of vascular cells, not vasoconstriction. Recognition of the pivotal role of cellular proliferation and transforming growth factor β (TGF-β) signaling paved the way for a new approach to the treatment of PAH. In the Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PULSAR), sotatercept, a fusion protein that impairs activation of a TGFβ pro-proliferative pathway, produced a greater reduction in pulmonary vascular resistance than placebo. Now studies are underway to assess the efficacy and safety of sotatercept across a broad spectrum of PAH disease severity.We have entered a new era of understanding and treating PAH, as genetics moves to center stage. This issue of Advances in Pulmonary Hypertension was organized to serve as a valuable resource for the PH community. The first article, authored by Drs. Carrie Welch and Wendy Chung of Columbia University, provides a comprehensive overview of the genomics of pulmonary hypertension. With this foundation in place, the second article, authored by Rachel Sullivan, MD (Stanford University) and Eric Austin, MD (Vanderbilt University) reviews the relationships between specific gene sequence variations and PAH phenotypes that clinicians are likely to encounter.In recent years genetic counseling and genetic testing have become important affordable services for patients with PAH and their families. Sumathi Rachamadugu, MSc, MS and Melanie Emmerson, MS (Intermountain Healthcare) collaborated with Barbara Girerd, PhD (Université Paris-Saclay) and Hunter Best, PhD (University of Utah) to provide an in depth introduction pretest genetic counseling, genetic testing, and posttest genetic counseling for PAH patients and their families. The PH Professional network contribution by Athena Angelopoulos, MS and Rachel Farrell, MS (University of California San Francisco) complements the preceding article by providing additional details related to genetic counseling and testing for PAH patients and their families.Finally, Drs. Austin, Chung, and Yu, joined us for a roundtable discussion on the genetics of pulmonary hypertension. Participants shared their personal knowledge of the history of genetic research and discovery related to PH, their advice on discussing genetic aspects of PH with patients and families, their thoughts about involving genetic counselors and ordering genetic tests, as well as how genetic test results influence treatment decisions and how knowledge of molecular pathways informs the development of new medications to treat PAH.In closing, we thank the authors and everyone at PHA and Allen Press who worked so hard to produce this issue of Advances.

Genetics of pulmonary hypertension and high-altitude pulmonary edema.

Heritable pulmonary arterial hypertension (PAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene and/or genes of its signaling pathway in ~85% of patients. A genetic predisposition to high-altitude pulmonary edema (HAPE) has long been suspected because of familial HAPE cases, but very few possibly disease-causing mutations have been identified to date. This minireview provides an overview of genetic analyses investigating common polymorphisms in HAPE-susceptible patients and the directed identification of disease-causing mutations in PAH patients. Increased pulmonary artery pressure is highlighted as an overlapping clinical feature of the two diseases. Moreover, studies showing increased pulmonary artery pressures in HAPE-susceptible patients during exercise or hypoxia as well as in healthy BMPR2 mutation carriers are illustrated. Finally, high-altitude pulmonary hypertension is introduced and future research perspectives outlined.

Pathobiology, pathology and genetics of pulmonary hypertension: Update from the Cologne Consensus Conference 2018

The European guidelines, which focus on clinical aspects of pulmonary hypertension (PH), provide only minimal information about the pathophysiological concepts of PH. Here, we review this topic in greater detail, focusing on specific aspects in the pathobiology, pathology and genetics, which include mechanisms of vascular inflammation, the role of transcription factors, ion channels/ion channel diseases, hypoxic pulmonary vasoconstriction, genetics/epigenetics, metabolic dysfunction, and the potential future role of histopathology of PH in the modern era of PH therapy. In addition to new insights in the pathobiology of this disease, this working group of the Cologne Consensus Conference also highlights novel concepts and potential new therapeutic targets to further improve the treatment options in PAH.

Genetics of pulmonary hypertension in the clinic.

Heritable pulmonary arterial hypertension (PAH) is an autosomal dominant disease with incomplete penetrance because of mutations in bone morphogenetic protein receptor-II (BMPR2), activin A receptor type II-like kinase 1, endoglin, caveolin-1, potassium channel subfamily K, member 3, and T-box gene 4 genes. Heritable pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH) is an autosomal recessive disease because of biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene. The 2015 european society of cardiology (ESC) and european respiratory society (ERS) pulmonary hypertension guidelines recommend genetic counselling and testing to adults and children with PAH or PVOD/PCH as well as in adult relatives at risk of carrying a predisposing mutation. In France, genetic counseling and testing are offered to all patients displaying sporadic or familial form of PAH or PVOD/PCH and to their relatives at high risk of carrying a predisposing mutation. Patients with a heritable form of PAH are younger at diagnosis with a worse hemodynamic and a dismal prognosis. Patients with a heritable form of PVOD/PCH are younger at diagnosis with a worse response to specific PAH therapies. A program to detect PAH in an early phase was offered to all asymptomatic BMPR2 mutation carriers, according to the 2015 ESC/ERS guidelines. Finally, preimplantation genetic diagnosis has been performed in families with a history of BMPR2 mutations. Genetic counseling and testing has to be implemented in pulmonary hypertension centers.

Genetics of pulmonary hypertension.

The identification of the genetic basis for heritable predisposition to pulmonary arterial hypertension (PAH) has altered the clinical and research landscape for PAH patients and their care providers. This review aims to describe the genetic discoveries and their impact on clinical medicine. Since the landmark discovery that bone morphogenetic protein receptor type II (BMPR2) mutations cause the majority of cases of familial PAH, investigators have discovered mutations in genes that cause PAH in families without BMPR2 mutations, including the type I receptor ACVRL1 and the type III receptor ENG (both associated with hereditary hemorrhagic telangiectasia), caveolin-1 (CAV1), and a gene (KCNK3) encoding a two-pore potassium channel. Mutations in these genes cause an autosomal-dominant predisposition to PAH in which a fraction of mutation carriers develop PAH (incomplete penetrance). In 2014, scientists discovered mutations in eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) that cause pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease, an autosomal recessively inherited disorder. The discovery that some forms of pulmonary hypertension are heritable and can be genetically defined adds important opportunities for physicians to educate their patients and their families to understand the potential risks and benefits of genetic testing.

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Genetics of pulmonary hypertension.

Pulmonary hypertension (PH) is a phenotype characterized by functional and structural changes in the pulmonary vasculature, leading to increased vascular resistance.[12] The World Health Organization has classified PH into five different types: arterial, venous, hypoxic, thromboembolic or miscellaneous; details are available in the main guidelines. Group I of this classification, designated as pulmonary arterial hypertension (PAH), will remain the main focus here. The pathophysiology involves signaling, endothelial dysfunction, activation of fibroblasts and smooth muscle cells, interaction between cells within the vascular wall, and the circulating cells; as a consequence plexiform lesions are formed, which is common to both idiopathic and heritable PAH but are also seen in other forms of PAH.[234] As the pathology of PAH in the lung is well known, this article focuses on the genetic aspects associated with the disease and is a gist of several available articles in literature.

Genetics of pulmonary hypertension: from bench to bedside.

Primary pulmonary hypertension has been described as either sporadic or clustered in families. Familial primary pulmonary hypertension segregates as an autosomal dominant trait with markedly reduced disease gene penetrance. Defects within bone morphogenetic protein receptor type II gene, coding for a receptor member of the transforming growth factor-beta family, underlie familial primary pulmonary hypertension. Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. In addition, a proportion of so-called sporadic primary pulmonary hypertension turns out to have an inherited basis, as demonstrated by germline bone morphogenetic protein receptor type II gene mutations. Analysis of cases in association with hereditary haemorrhagic telangiectasia led to the demonstration that pulmonary arterial hypertension can involve activin-receptor-like kinase 1 mutations, a type I transforming growth factor-beta receptor. These findings emphasise the critical role of the transforming growth factor-beta signalling pathway in pulmonary arterial hypertension. While this achievement has generated extreme interest, the pathobiology of severe pulmonary arterial hypertension remains unclear and genomic approaches to pulmonary hypertension research may identify additional molecular determinants for this disorder. Finally, there is an urgent need to develop relevant guidelines for genetic counselling to assist patients, their relatives and pulmonary vascular specialists to utilise these recent observations.