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Genetics and Genomics of Pulmonary Arterial Hypertension

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (10 September 2020) | Viewed by 37837

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Special Issue Editors

Dr. Laura Southgate

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Guest Editor

Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK
Interests: rare disease; medical genetics; human genomics; vascular disease

Dr. Rajiv Machado

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Guest Editor

Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK
Interests: pulmonary arterial hypertension; rare and common genetic variation in pulmonary arterial hypertension; next generation sequencing analysis of childhood pulmonary arterial hypertension; genetic factors underlying Adams-Oliver syndrome; analysis of under-studied patient populations in rare disease

Special Issue Information

Dear Colleagues,

Pulmonary arterial hypertension (PAH) is a severe and progressive vascular disorder, which typically manifests at around 30–40 years of age and is often fatal. Pathogenic mutation of the bone morphogenetic protein receptor type 2 (BMPR2) gene is the major PAH risk factor, with over 480 distinct variants reported to date. However, PAH demonstrates substantial locus heterogeneity and missing heritability, particularly in sporadic disease. Whilst BMPR2 mutations account for up to 86% of familial PAH, the vast majority of idiopathic cases remain genetically unresolved. In addition, the genetic aetiology of childhood-onset disease is often more heterogeneous with a poorer prognosis, necessitating dedicated studies to improve molecular diagnosis and clinical management.

With the advent of next-generation sequencing, there has been an explosion of new findings in PAH, expanding the genetic architecture of idiopathic disease and highlighting numerous additional risk factors and novel pathways for exploration. In this Special Issue, we aim to provide an overview of the advancements in PAH genetics and genomics over the past decade, and to examine the emerging interplay between genotype and phenotypic outcomes. We also seek to discuss the role of epigenetics and common variation in the pathogenesis of PAH.

Dr. Laura Southgate
Dr. Rajiv Machado
Guest Editors

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Keywords

Pulmonary arterial hypertension
Genomics of pulmonary hypertension
Next-generation sequencing
Cardiovascular genetics
Epigenetics
Genotype–phenotype correlation
Personalised medicine

Published Papers (11 papers)

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Editorial

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4 pages, 197 KiB

Open AccessEditorial

Pulmonary Arterial Hypertension: A Deeper Evaluation of Genetic Risk in the -Omics Era

by Rajiv D. Machado and Laura Southgate

Genes 2021, 12(11), 1798; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111798 - 16 Nov 2021

Viewed by 1703

Abstract

Pulmonary arterial hypertension (PAH) is a highly heterogeneous disorder with a complex, multifactorial aetiology [...] Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

Research

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12 pages, 966 KiB

Open AccessArticle

Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension

by Simone M. Gelinas, Clare E. Benson, Mohammed A. Khan, Rolf M. F. Berger, Richard C. Trembath, Rajiv D. Machado and Laura Southgate

Genes 2020, 11(11), 1328; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111328 - 11 Nov 2020

Cited by 13 | Viewed by 3521

Abstract

Pulmonary arterial hypertension (PAH) describes a rare, progressive vascular disease caused by the obstruction of pulmonary arterioles, typically resulting in right heart failure. Whilst PAH most often manifests in adulthood, paediatric disease is considered to be a distinct entity with increased morbidity and often an unexplained resistance to current therapies. Recent genetic studies have substantially increased our understanding of PAH pathogenesis, providing opportunities for molecular diagnosis and presymptomatic genetic testing in families. However, the genetic architecture of childhood-onset PAH remains relatively poorly characterised. We sought to investigate a previously unsolved paediatric cohort (n = 18) using whole exome sequencing to improve the molecular diagnosis of childhood-onset PAH. Through a targeted investigation of 26 candidate genes, we applied a rigorous variant filtering methodology to enrich for rare, likely pathogenic variants. This analysis led to the detection of novel PAH risk alleles in five genes, including the first identification of a heterozygous ATP13A3 mutation in childhood-onset disease. In addition, we provide the first independent validation of BMP10 and PDGFD as genetic risk factors for PAH. These data provide a molecular diagnosis in 28% of paediatric cases, reflecting the increased genetic burden in childhood-onset disease and highlighting the importance of next-generation sequencing approaches to diagnostic surveillance. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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12 pages, 870 KiB

Open AccessArticle

Expression Quantitative Trait Locus Mapping in Pulmonary Arterial Hypertension

by Anna Ulrich, Pablo Otero-Núñez, John Wharton, Emilia M. Swietlik, Stefan Gräf, Nicholas W. Morrell, Dennis Wang, Allan Lawrie, Martin R. Wilkins, Inga Prokopenko, Christopher J. Rhodes, on behalf of The NIHR BioResource—Rare Diseases Consortium and UK PAH Cohort Study Consortium

Genes 2020, 11(11), 1247; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111247 - 22 Oct 2020

Cited by 4 | Viewed by 2607

Abstract

Expression quantitative trait loci (eQTL) can provide a link between disease susceptibility variants discovered by genetic association studies and biology. To date, eQTL mapping studies have been primarily conducted in healthy individuals from population-based cohorts. Genetic effects have been known to be context-specific and vary with changing environmental stimuli. We conducted a transcriptome- and genome-wide eQTL mapping study in a cohort of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) using RNA sequencing (RNAseq) data from whole blood. We sought confirmation from three published population-based eQTL studies, including the GTEx Project, and followed up potentially novel eQTL not observed in the general population. In total, we identified 2314 eQTL of which 90% were cis-acting and 75% were confirmed by at least one of the published studies. While we observed a higher GWAS trait colocalization rate among confirmed eQTL, colocalisation rate of novel eQTL reported for lung-related phenotypes was twice as high as that of confirmed eQTL. Functional enrichment analysis of genes with novel eQTL in PAH highlighted immune-related processes, a suspected contributor to PAH. These potentially novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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12 pages, 706 KiB

Open AccessArticle

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients

by Lieke M. van den Heuvel, Samara M. A. Jansen, Suzanne I. M. Alsters, Marco C. Post, Jasper J. van der Smagt, Frances S. Handoko-De Man, J. Peter van Tintelen, Hans Gille, Imke Christiaans, Anton Vonk Noordegraaf, HarmJan Bogaard and Arjan C. Houweling

Genes 2020, 11(10), 1191; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101191 - 13 Oct 2020

Cited by 10 | Viewed by 2565

Abstract

Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 BMPR2 and SMAD9 negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 (N = 4), GDF2 (N = 2), EIF2AK4 (N = 1), and TBX4 (N = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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12 pages, 1134 KiB

Open AccessArticle

BMPR2 Promoter Variants Effect Gene Expression in Pulmonary Arterial Hypertension Patients

by Jie Song, Katrin Hinderhofer, Lilian T. Kaufmann, Nicola Benjamin, Christine Fischer, Ekkehard Grünig and Christina A. Eichstaedt

Genes 2020, 11(10), 1168; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101168 - 06 Oct 2020

Cited by 2 | Viewed by 3911

Abstract

Pathogenic variants have been identified in 85% of heritable pulmonary arterial hypertension (PAH) patients. These variants were mainly located in the bone morphogenetic protein receptor 2 (BMPR2) gene. However, the penetrance of BMPR2 variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic BMPR2 promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify BMPR2 promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. BMPR2 promoter variants were identified in PAH patients and cloned into plasmids. These were transfected into human pulmonary artery smooth muscle cells to determine their respective transcriptional activity. Nine different BMPR2 promoter variants were identified in seven PAH families and three idiopathic PAH patients. Seven of the variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-930_-928dupGGC, c.-933_-928dupGGCGGC, c.-930_-928delGGC and c.-1141C>T) led to a significantly decreased transcriptional activity. This study identified novel BMPR2 promoter variants which may affect BMPR2 gene expression in PAH patients. They could contribute to disease manifestations at least in some families. Further studies are needed to investigate the frequency of BMPR2 promoter variants and their impact on penetrance and disease manifestation. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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15 pages, 2339 KiB

Open AccessArticle

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

by Jair Antonio Tenorio Castaño, Ignacio Hernández-Gonzalez, Natalia Gallego, Carmen Pérez-Olivares, Nuria Ochoa Parra, Pedro Arias, Elena Granda, Gonzalo Gómez Acebo, Mauro Lago-Docampo, Julian Palomino-Doza, Manuel López Meseguer, María Jesús del Cerro, Spanish PAH Consortium, Diana Valverde, Pablo Lapunzina and Pilar Escribano-Subías

Genes 2020, 11(10), 1158; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101158 - 30 Sep 2020

Cited by 18 | Viewed by 3068

Abstract

Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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Review

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10 pages, 261 KiB

Open AccessReview

Novel Advances in Modifying BMPR2 Signaling in PAH

by Svenja Dannewitz Prosseda, Md Khadem Ali and Edda Spiekerkoetter

Genes 2021, 12(1), 8; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010008 - 23 Dec 2020

Cited by 16 | Viewed by 4188

Abstract

Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary arteries, that is characterized by progressive narrowing of the pulmonary arterial lumen and increased pulmonary vascular resistance, ultimately leading to right ventricular dysfunction, heart failure and premature death. Current treatments mainly target pulmonary vasodilation and leave the progressive vascular remodeling unchecked resulting in persistent high morbidity and mortality in PAH even with treatment. Therefore, novel therapeutic strategies are urgently needed. Loss of function mutations of the Bone Morphogenetic Protein Receptor 2 (BMPR2) are the most common genetic factor in hereditary forms of PAH, suggesting that the BMPR2 pathway is fundamentally important in the pathogenesis. Dysfunctional BMPR2 signaling recapitulates the cellular abnormalities in PAH as well as the pathobiology in experimental pulmonary hypertension (PH). Approaches to restore BMPR2 signaling by increasing the expression of BMPR2 or its downstream signaling targets are currently actively explored as novel ways to prevent and improve experimental PH as well as PAH in patients. Here, we summarize existing as well as novel potential treatment strategies for PAH that activate the BMPR2 receptor pharmaceutically or genetically, increase the receptor availability at the cell surface, or reconstitute downstream BMPR2 signaling. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

56 pages, 2775 KiB

Open AccessReview

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

by Emilia M. Swietlik, Matina Prapa, Jennifer M. Martin, Divya Pandya, Kathryn Auckland, Nicholas W. Morrell and Stefan Gräf

Genes 2020, 11(12), 1408; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121408 - 26 Nov 2020

Cited by 11 | Viewed by 4542

Abstract

Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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10 pages, 1122 KiB

Open AccessReview

At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

by Meghan M. Cirulis, Mark W. Dodson, Lynn M. Brown, Samuel M. Brown, Tim Lahm and Greg Elliott

Genes 2020, 11(11), 1371; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111371 - 20 Nov 2020

Cited by 5 | Viewed by 3386

Abstract

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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18 pages, 1500 KiB

Open AccessReview

DNA Damage and Repair in Pulmonary Arterial Hypertension

by Samantha Sharma and Micheala A. Aldred

Genes 2020, 11(10), 1224; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101224 - 19 Oct 2020

Cited by 22 | Viewed by 3564

Abstract

Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with both genetic and environmental dynamics contributing to disease progression. Over the last decade, several studies have demonstrated the presence of genomic instability and increased levels of DNA damage in PAH lung vascular cells, which contribute to their pathogenic apoptosis-resistant and proliferating characteristics. In addition, the dysregulated DNA damage response pathways have been indicated as causal factors for the presence of persistent DNA damage. To understand the significant implications of DNA damage and repair in PAH pathogenesis, the current review summarizes the recent advances made in this field. This includes an overview of the observed DNA damage in the nuclear and mitochondrial genome of PAH patients. Next, the irregularities observed in various DNA damage response pathways and their role in accumulating DNA damage, escaping apoptosis, and proliferation under a DNA damaging environment are discussed. Although the current literature establishes the pertinence of DNA damage in PAH, additional studies are required to understand the temporal sequence of the above-mentioned events. Further, an exploration of different types of DNA damage in conjunction with associated impaired DNA damage response in PAH will potentially stimulate early diagnosis of the disease and development of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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16 pages, 4014 KiB

Open AccessReview

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

by Carrie L. Welch and Wendy K. Chung

Genes 2020, 11(10), 1213; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101213 - 16 Oct 2020

Cited by 23 | Viewed by 3645

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders. Full article

(This article belongs to the Special Issue Genetics and Genomics of Pulmonary Arterial Hypertension)

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