Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze the Bone Morphogenetic Protein Receptor 2 (BMPR2), Activin A type II receptor like kinase 1 (ALK1/ACVRL1) and potassium voltage-gated channel, shakerrelated subfamily, member 5 (KCNA5) genes in patients with idiopathic and associated PAH. Correlation among pathogenic mutations and clinical and functional parameters was further analyzed. Methods and results: Forty one patients and fifty controls were included in this study. Analysis of BMPR2, ACVRL1 and KCNA5 genes was performed by polymerase chain reaction (PCR) and direct sequencing. Fifty one nucleotide changes were detected in these genes in 40 of the 41 patients; only 22 of these changes, which were classified as pathogenic, have been detected in 21 patients (51.2%). Ten patients (62.5%) with idiopathic PAH and 10 (40%) with associated PAH showed pathogenic mutations in some of the three genes. Several clinical and hemodynamics parameters showed significant differences between carriers and non-carriers of mutations, being more severe in carriers: mean pulmonary artery pressure (p = 0.043), pulmonary vascular resistence (p = 0.043), cardiac index (p = 0.04) and 6 minute walking test (p = 0.02). This differences remained unchanged after adjusting for PAH type (idiopathic vs non idiopathic). Conclusions: Pathogenic mutations in BMPR2 gene are frequent in patients with idiopathic and associated PAH group I. Mutations in ACVRL1 and KCNA5 are less frequent. The presence of these mutations seems to increase the severity of the disease

Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects.

Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools

Genetics and Genomics of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a severe and progressive disorder affecting the blood vessels in the lungs. Typically, symptoms first appear at around 30–40 years of age and, without treatment, can lead to fatal heart disease within a few years. Genetic studies over the past decade have identified numerous genes that contribute to disease progression but, for many sufferers, the underlying genetic cause remains elusive. The collection of reviews and original research articles contained within this book provide an overview of recent advancements in understanding the genetic risk factors for pulmonary arterial hypertension. We further examine the emerging interplay between genetic variants and clinical outcomes, providing a framework for new treatments and improved patient care

The BMPR2, ALK1 and ENG Genes Mutation in Congenital Heart DiseaseAssociated Pulmonary Artery Hypertension

The gene mutation is one of the background underlie the pathogenesis of pulmonary artery hypertension (PAH). Several genes have been recognized to be responsible for the development of PAH. The mutation in transforming growth factor-β (TGF-β) pathway is considered to be major genotype background in heritable PAH. The genetic mutation in bone morphogenetic protein receptor-2 (BMPR2), activin receptor-like kinase 1 (ALK-1) and endoglin (ENG) are known to cause heritable PAH. In congenital heart disease–associated PAH (CHDAPAH), their mutation are also presence

Clinical Heterogeneity of Pulmonary Arterial Hypertension Associated With Variants in TBX4

Background: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. Methods: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. Results: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. Conclusions: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.This project was founded by Project "Bases Gene´tico Moleculares de la Medicina de Precisio´n en la Hipertensio´n Arterial Pulmonar". Funder: Instituto Carlos III. Ministerio de Economı´a y Competitividad. https://www.isciii.es/Paginas/Inicio.aspx Award number: PI 18/01233 Grant Recipient: P E-

Phenotype – genotype associations in a large cohort of patients with pulmonary arterial hypertension

Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare diseases with a poor prognosis. There is significant heterogeneity in clinical features at diagnosis, and in a proportion of patients there is a genetic cause of the disease. This clinical and genetic heterogeneity has hindered accurate risk stratification and the development of personalised treatments. The National Institute of Health Research BioResource – Rare Diseases PAH Study and the Medical Research Council / British Heart Foundation National Cohort Study of Idiopathic and Heritable PAH were established to investigate disease pathogenesis through whole genome sequencing and deep phenotyping. One thousand and seventy patients were sequenced and 391 clinical variables were captured for each patient. In patients with idiopathic PAH the age at diagnosis, gender, right atrial pressure and the transfer coefficient for carbon monoxide were identified as independent prognostic variables. However, the presence of rare and predicted deleterious variants in BMPR2 was not of prognostic significance. Variants in genes previously associated with disease pathogenesis were identified in 204 patients (19 %). Patients with variants in BMPR2 were younger at diagnosis and had more severe pulmonary haemodynamic impairment compared to patients with idiopathic PAH. Novel associations between BMPR2 variant status and both haemoglobin concentration and white blood cell count were observed. Four patients carried variants in both SMAD9 and either BMPR2 or EIF2AK4. The clinical significance of this requires further study. Unexpectedly, biallelic variants in EIF2AK4 were identified in patients with a clinical diagnosis of idiopathic PAH. These patients had a significantly worse prognosis compared to patients with idiopathic PAH. The spectrum of phenotypic, radiological and histological changes associated with biallelic EIF2AK4 variants was broader than previously recognised. As these datasets mature, further analyses assessing the response to specific treatments and the outcomes of specific subgroups will be possible.NIHR RD TR

The Action of Smooth Muscle Cell Potassium Channels in the Pathology of Pulmonary Arterial Hypertension

Many different types of potassium channels with various functions exist in pulmonary artery smooth muscle cells, contributing to many physiological actions and pathological conditions. The deep involvement of these channels in the onset and exacerbation of pulmonary arterial hypertension (PAH) also continues to be revealed. In 2013, KCNK3 (TASK1), which encodes a type of two-pore domain potassium channel, was shown to be a predisposing gene for PAH by genetic mutation, and it was added to the PAH classification at the Fifth World Symposium on Pulmonary Hypertension (Nice International Conference). Decreased expression and inhibited activity of voltage-gated potassium channels, particularly KCNA5 (Kv1.5), are also seen in PAH, regardless of the cause, and facilitation of pulmonary arterial contraction and vascular remodeling has been shown. The calcium-activated potassium channels seen in smooth muscle cells also change from BKca (Kca1.1) to IKca (Kca3.1) predominance in PAH due to transformation, and have effects including the facilitation of smooth muscle cell migration, enhancement of proliferation, and inhibition of apoptosis. Elucidation of these roles for potassium channels in pulmonary vasoconstriction and remodeling may help bring new therapeutic strategies into view

Bases genéticas en la población española con hipertensión arterial pulmonar idiopática o hereditaria y enfermedad venooclusiva pulmonar. Implicaciones clínicas actuales

La hipertensión arterial pulmonar (HAP) es una enfermedad rara caracterizada por el remodelado de pequeñas arteriolas pulmonares que conduce al aumento progresivo de la resistencia vascular pulmonar, fracaso ventricular derecho y eventual muerte. Se asocia con diversas condiciones clínicas, pudiendo presentarse como formas idiopáticas y hereditarias, habitualmente de presentación en la edad adulta joven. Durante muchos años el gen BMPR2 ha sido el único conocido relacionado con el desarrollo de HAP hereditaria, de herencia autosómico dominante, penetrancia incompleta y expresividad variable, caracterizándose por formas tempranas de presentación, mayor severidad hemodinámica y curso clínico más grave. Sin embargo, recientes avances en el campo de la genética han permitido el descubrimiento de nuevos genes responsables, como KCNK3 y TBX4, entre otros, cuyos fenotipos clínicos asociados han sido escasamente descritos. Por otro lado, la enfermedad venooclusiva pulmonar (EVOP) hereditaria es una forma rara de HAP consistente en la afectación predominante de las vénulas pulmonares, que conduce de manera análoga a un aumento de la resistencia vascular pulmonar, fallo ventricular derecho y muerte. Se caracteriza por la reducción de la capacidad de difusión del monóxido de carbono, edades tempranas de presentación y un curso clínico agresivo, con mala respuesta al tratamiento con vasodilatadores pulmonares con eventual desarrollo de edema pulmonar. Hasta la fecha sólo se ha descrito un gen relacionado con el desarrollo de EVOP hereditaria, el gen EIF2AK4, de herencia autosómica recesiva y elevada penetrancia. La población española con HAP idiopática y hereditaria ha sido escasamente descrita, siendo desconocido el papel de las distintas alteraciones genéticas. Por otro lado, no existen estudios previos en nuestro país referentes a la EVOP hereditaria. La presente Tesis Doctoral recoge la mayor cohorte de pacientes con HAP idiopática y hereditaria estudiada en nuestro país y la única de pacientes con EVOP hereditaria, de etnia gitana y marcada consanguineidad, incluidos en el marco del Estudio Multicéntrico Español de genética de HAP. El objetivo es analizar la prevalencia de las distintas alteraciones genéticas en la población española de HAP idiopática y hereditaria, estudiar genéticamente la población española de etnia gitana con EVOP hereditaria y describir el fenotipo clínico y pronóstico asociado a cada una de las alteraciones genéticas estudiadas, así como llevar a cabo el cribado de familiares. A pesar de los avances experimentados en materia de diagnóstico y tratamiento, el pronóstico de ambas entidades sigue siendo muy pobre con una breve supervivencia libre de muerte o trasplante pulmonar, a día de hoy el único tratamiento eficaz. Quizás el creciente conocimiento en el campo de la genética permita en un futuro, no sólo el diagnóstico precoz y consejo reproductivo dirigido a prevenir la aparición de nuevos casos, sino además, el diseño de un plan terapéutico individualizado para cada paciente en función del perfil genético hallado, que permita optimizar los recursos y los resultados clínicos obtenidos

Development of computational approaches for whole-genome sequence variation and deep phenotyping

The rare disease pulmonary arterial hypertension (PAH) results in high blood pressure in the lung caused by narrowing of lung arteries. Genes causative in PAH were discovered through family studies and very often harbour rare variants. However, the genetic cause in heritable (31%) and idiopathic (79%) PAH cases is not yet known but are speculated to be caused by rare variants. Advances in high-throughput sequencing (HTS) technologies made it possible to detect variants in 98% of the human genome. A drop in sequencing costs made it feasible to sequence 10,000 individuals including 1,250 subjects diagnosed with PAH and relatives as part of the NIHR Bioresource – Rare (BR-RD) disease study. This large cohort allows the genome-wide identification of rare variants to discover novel causative genes associated with PAH in a case-control study to advance our understanding of the underlying aetiology. In the first part of my thesis, I establish a phenotype capture system that allows research nurses to record clinical measurements and other patient related information of PAH patients recruited to the NIHR BR-RD study. The implemented extensions provide a programmatic data transfer and an automated data release pipeline for analysis ready data. The second part is dedicated to the discovery of novel disease genes in PAH. I focus on one well characterised PAH disease gene to establish variant filter strategies to enrich for rare disease causing variants. I apply these filter strategies to all known PAH disease genes and describe the phenotypic differences based on clinically relevant values. Genome-wide results from different filter strategies are tested for association with PAH. I describe the findings of the rare variant association tests and provide a detailed interrogation of two novel disease genes. The last part describes the data characteristics of variant information, available non SQL (NoSQL) implementations and evaluates the suitability and scalability of distributed compute frameworks to store and analyse population scale variation data. Based on the evaluation, I implement a variant analysis platform that incrementally merges samples, annotates variants and enables the analysis of 10,000 individuals in minutes. An incremental design for variant merging and annotation has not been described before. Using the framework, I develop a quality score to reduce technical variation and other biases. The result from the rare variant association test is compared with traditional methods

Vitamina D en la hipertensión pulmonar

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 01-04-2022Pulmonary arterial hypertension (PAH) is a vascular chronic disorder, characterized by sustained vasoconstriction, vascular remodelling, thrombosis in situ and inflammation. Although there have been important advances in the knowledge of its pathophysiology and consequently of its pharmacological treatments, PAH remains a debilitating, limiting and rapidly progressive disease. In recent years, epidemiological, nutritional studies and animal models have reported an association between nutritional factors and PAH. Moreover, some authors suggest that nutritional intervention may be a new preventive strategy in PAH. Vitamin D (vitD) deficiency is a worldwide health problem of pandemic proportions. Preliminary studies have suggested that vitD deficiency is more prevalent in PAH patients than in general population. There are some basic and clinic evidences which suggest that hypovitaminosis D may negatively impact on disease progression. The active form of vitD, i.e.,calcitriol, exerts its functions through the vitamin D receptor (VDR), which acts as a transcription factor, regulating changes in gene expression. The discovery of VDR in many tissues and cell types that do not participate in calcium and phosphorous homeostasis, (the main functions of calcitriol), led to identify a great variety of functions mediated by VDR, and of potential relevance in the cardiovascular system, such as cell proliferation, differentiation, control of vascular tone or immunomodulation...La hipertensión arterial pulmonar (HAP) es una enfermedad vascular crónica, caracterizada por una vasoconstricción sostenida, remodelado vascular, trombosis in situ e inflamación en las arterias pulmonares (AP). A pesar de los importantes avances en el conocimiento de su fisiopatología y consecuentemente la identificación de terapias farmacológicas, la HAP continúa siendo una enfermedad debilitante, limitante y progresiva. En los últimos años, estudios epidemiológicos, nutricionales, así como modelos animales han identificado una asociación entre factores nutricionales e HAP; incluso algunos autores sugieren que la intervención nutricional podría ser una nueva estrategia preventiva en pacientes con HAP. La deficiencia de vitamina D (vitD) es un problema de salud a nivel global de proporciones pandémicas, incluso se estima que es más prevalente en pacientes con HAP que en la población en general. Existen algunas evidencias que sugieren que la deficiencia de vit Dpuede tener un impacto negativo en progresión de dicha patología. La forma activa de la vitD, denominada calcitriol ejerce sus funciones a través del receptor de vitD (VDR), que actúa como un factor de transcripción, regulando la expresión de genes diana. El descubrimiento de VDR en diversos tejidos y células, que no participan en la homeostasis del calcio y el fósforo (las principales funciones del calcitriol), permitió la identificación de una gran variedad defunciones mediadas por VDR con gran relevancia a nivel cardiovascular, como, por ejemplo, la regulación de la proliferación y diferenciación celular, control del tono vascular e inmunomodulación...Fac. de MedicinaTRUEunpu