Genetics and genomics of pulmonary arterial hypertension

Florent Soubrier; Wendy K Chung; Rajiv Machado; Ekkehard Grünig; Micheala Aldred; Mark Geraci; James E Loyd; C Gregory Elliott; Richard C Trembath; John H Newman; Marc Humbert

doi:10.1016/j.jacc.2013.10.035

Genetics and genomics of pulmonary arterial hypertension

Florent Soubrier, Wendy K Chung, Rajiv Machado, Ekkehard Grünig, Micheala Aldred, Mark Geraci, James E Loyd, C Gregory Elliott, Richard C Trembath, John H Newman, Marc Humbert

Research output: Contribution to journal › Article › peer-review

273 Citations (Scopus)

Abstract

Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.

Original language	English
Pages (from-to)	D13-21
Journal	Journal of the American College of Cardiology
Volume	62
Issue number	25 Suppl
DOIs	https://doi.org/10.1016/j.jacc.2013.10.035
Publication status	Published - 24 Dec 2013

Keywords

Animals
Bone Morphogenetic Protein Receptors, Type II
Familial Primary Pulmonary Hypertension
Genetic Predisposition to Disease
Genome-Wide Association Study
Genomics
Humans
Hypertension, Pulmonary
Mutation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2013.10.035

Cite this

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title = "Genetics and genomics of pulmonary arterial hypertension",

abstract = "Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.",

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doi = "10.1016/j.jacc.2013.10.035",

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T1 - Genetics and genomics of pulmonary arterial hypertension

AU - Soubrier, Florent

AU - Chung, Wendy K

AU - Machado, Rajiv

AU - Grünig, Ekkehard

AU - Aldred, Micheala

AU - Geraci, Mark

AU - Loyd, James E

AU - Elliott, C Gregory

AU - Trembath, Richard C

AU - Newman, John H

AU - Humbert, Marc

PY - 2013/12/24

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N2 - Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.

AB - Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.

KW - Animals

KW - Bone Morphogenetic Protein Receptors, Type II

KW - Familial Primary Pulmonary Hypertension

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genomics

KW - Humans

KW - Hypertension, Pulmonary

KW - Mutation

U2 - 10.1016/j.jacc.2013.10.035

DO - 10.1016/j.jacc.2013.10.035

M3 - Article

C2 - 24355637

SN - 0735-1097

VL - 62

SP - D13-21

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 25 Suppl

ER -

Genetics and genomics of pulmonary arterial hypertension

Abstract

Keywords

UN SDGs

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