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Genetics of Pulmonary Vascular Disease

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Pulmonary Hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditary (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognized and are usually due to mutations in the Bone Morphogenetic Protein Receptor type 2 gene (BMPR2). Less commonly mutations in Activin-like Kinase-Type I (ALK1), Endoglin (ENG), Mothers against decapentaplegic 8 (SMAD8), Mothers against decapentaplegic 4 (SMAD4), Caveolin 1 (CAV1), and the two pore domain potassium channel subfamily K, member 3 (KCNK3) can cause hereditary pulmonary hypertension. Approximately 20 % of patients with IPAH carry mutations in BMPR2 and rarely mutations in other genes are associated with familial PAH. With advances in genomic technology and with international collaborative efforts, genome-wide association studies (GWAS) have identified polymorphisms in Cerebellin 2 (CBLN2) to increase the risk of PAH by twofold. Clinical testing for BMPR2 and other genes associated with PAH is available and may be offered to HPAH and IPAH patients and should be preceded by genetic counseling, since lifetime penetrance for BMPR2 is only 20 %. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers, and, thus, will not require lifelong surveillance.

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Abbreviations

ACD/MPV:

Alveolar capillary dysplasia with misalignment of the pulmonary veins

AK:

Adenylate kinase

ALK1:

Activin-like Kinase-Type I

ALK6:

Activin Receptor-like Kinase-6

ANCAs:

Anti-neutrophil cytoplasmic antibodies

AT-III:

Antithrombin III ATS: Arterial tortuosity syndrome

BAX:

BCL-2 associated X-protein

BMPR2:

Bone Morphogenetic Protein Receptor type 2 gene

BMPRIB:

BMP receptor type IB

CAV1:

Caveolin 1

CBLN2:

Cerebellin 2

CCB:

Calcium channel blockade

CHD:

Congenital heart disease

COL3A1:

Type III collagen

COPD:

Chronic obstructive pulmonary disease

CSS:

Churg-strauss syndrome

CTEPH:

Chronic thrombotic embolic pulmonary hypertension

EIF2AK4:

Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4

ENG:

Endoglin

F5:

Coagulation factor V

FOXF1:

Forkhead box F1

G-6-PD:

Glucose-6-phosphate dehydrogenase

GCA:

Giant cell arteritis

GLUT10:

Glucose transporter 10

HDACs:

Histone deacetylases

HHT:

Hereditary hemorrhagic telangiectasia

HIF-1α:

Hypoxia inducible factor 1α

HIV:

Human immunodeficiency virus

HK:

Hexokinase

HLA:

Human leukocyte antigen

HPAH:

Hereditary pulmonary arterial hypertension

HPS:

Hepatopulmonary syndrome

IL12B:

Interleukin 12B

IPAH:

Idiopathic pulmonary arterial hypertension

KCNK3:

Potassium Channel subfamily K, member 3

MTHFR:

Methylenetetrahydrofolate reductase

NT5C3A:

uridine 5-prime monophosphate hydrolase

PAH:

Pulmonary arterial hypertension

PAVMs:

Pulmonary arteriovenous malformations

PCH:

Pulmonary capillary hemangiomatosis

PE:

Pulmonary emboli

PFK:

Phosphofructokinase

PGK1:

Phosphoglycerate kinase 1

PK:

Pyruvate kinase

PON1:

Paraoxonase 1

PPHN:

Persistent pulmonary hypertension of the newborn

PTPN22:

protein tyrosine phosphatases nonreceptor- type 22

PVH:

Pulmonary venous hypertension

PVOD:

Pulmonary veno-occlusive disease

RBC:

Red blood cell

SCD:

Sickle cell disease

SERPINA1:

Serpin peptidase inhibitor clade A, member 1

SLC2A10:

Solute carrier family 2 member 10

SMAD1:

Mothers against decapentaplegic 1

SMAD2:

Mothers against decapentaplegic 2

SMAD3:

Mothers against decapentaplegic 3

SMAD4:

Mothers against decapentaplegic 4

SMAD8:

Mothers against decapentaplegic 8

SOD2:

Superoxide dismutase 2

SSc:

Systemic sclerosis

TBX2:

T-box transcription factor-2

TBX4:

T-box transcription factor-4

TGFβ:

Transforming growth factor β

TGFBR2:

TGF-β receptor II

TMEM70:

Transmembrane protein 70

VTE:

Venous thromboembolism

GWAS:

Genome-wide association study

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Authors and Affiliations

  1. Molecular Genetics in Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, 10032, NY, USA

    Lijiang Ma MD, PhD

  2. Pediatrics, Columbia University Medical Center, New York, NY, USA

    Lijiang Ma MD, PhD

  3. Molecular Genetics in Departments of Pediatrics and Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, 10032, NY, USA

    Wendy K. Chung MD, PhD

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Correspondence to Wendy K. Chung MD, PhD .

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  1. Cardiovascular Medicine Dept, Harvard Medical School Brigham and Women’s Hospital, Boston, Massachusetts, USA

    Bradley A. Maron

  2. Pulmonary & Critical Care Medicine, Stanford University Medical Center, Stanford, California, USA

    Roham T. Zamanian

  3. Pulmonary Critical Care Medicine Dept Cardiovascular Medicine Dept, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, USA

    Aaron B. Waxman

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Ma, L., Chung, W.K. (2016). Genetics of Pulmonary Vascular Disease. In: Maron, B., Zamanian, R., Waxman, A. (eds) Pulmonary Hypertension. Springer, Cham. https://doi.org/10.1007/978-3-319-23594-3_6

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