State-of-the-Art Paper
Genetics and Genomics of Pulmonary Arterial Hypertension

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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.

Key Words

BMPR2
genetics
genomic
pulmonary hypertension

Abbreviations and Acronyms

BMP
bone morphogenetic protein
CHD
congenital heart disease
GINA
Genetic Information Non-Discrimination Act
GSD
glycogen storage disease
HDAC
histone deacetylase
HHT
hereditary hemorrhagic telangiectasia
HPAH
heritable pulmonary arterial hypertension
IL
interleukin
IPAH
idiopathic pulmonary arterial hypertension
mRNA
messenger ribonucleic acid
miRNA
micro ribonucleic acid
PAEC
pulmonary artery endothelial cell
PAH
pulmonary arterial hypertension
PASMC
pulmonary artery smooth muscle cell
SNP
single nucleotide polymorphism
TGF
transforming growth factor

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Dr. Machado has received institutional grant support from Actelion and United Therapeutics; and is on the advisory board of United Therapeutics and Gilead. Dr. Grünig has served on the advisory board of Bayer Healthcare, Actelion, GlaxoSmithKline, Eli Lilly, Novartis, United Therapeutics, Alexion, and Pfizer; and has received consultancy and lecture fees from Bayer Healthcare Pharmaceuticals, Actelion, GlaxoSmithKline, Eli Lilly, Novartis, United Therapeutics, Pfizer, and Alexion. Dr. Geraci has served on the Medical Advisory Board for Flight Attendants Medical Research Institute. Dr. Elliott is employed by Intermountain Healthcare, which has received research grants from Actelion, Bayer, GeNO, Gilead, National Institutes of Health, and United Therapeutics for which he has acted as Principal Investigator; and he has received honoraria and/or consulting fees from Ikaria, CoTherix, and Boehringer Ingelheim. Dr. Humbert has served on the scientific advisory board of and as an investigator for trials involving Actelion, Aires, Bayer, GlaxoSmithKline, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.