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Molecular genetic framework underlying pulmonary arterial hypertension.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Gräf, Stefan 
Morrell, Nicholas W  ORCID logo  https://orcid.org/0000-0001-5700-9792

Abstract

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of high-throughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal-dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications for lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention.

Description

Keywords

Animals, Arterial Pressure, Genetic Predisposition to Disease, Genetic Variation, Humans, Phenotype, Prognosis, Pulmonary Arterial Hypertension, Pulmonary Artery, Risk Factors, Vascular Remodeling

Journal Title

Nat Rev Cardiol

Conference Name

Journal ISSN

1759-5002
1759-5010

Volume Title

17

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (MR/K020919/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
British Heart Foundation (None)
British Heart Foundation (SP/18/10/33975)