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Review
. 2019 Jan 24;53(1):1801899.
doi: 10.1183/13993003.01899-2018. Print 2019 Jan.

Genetics and genomics of pulmonary arterial hypertension

Nicholas W Morrell  1 , Micheala A Aldred  2 , Wendy K Chung  3 , C Gregory Elliott  4 , William C Nichols  5 , Florent Soubrier  6 , Richard C Trembath  7 , James E Loyd  8
Affiliations
Review

Genetics and genomics of pulmonary arterial hypertension

Nicholas W Morrell et al. Eur Respir J. .

Abstract

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25-30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.

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Conflict of interest statement

Conflict of interest: N.W. Morrell reports grants and personal fees from Morphogen-IX, outside the submitted work. Conflict of interest: M.A. Aldred reports grants from the NIH, during the conduct of the study. Conflict of interest: W.K. Chung has nothing to disclose. Conflict of interest: C.G. Elliott reports personal fees for steering committee work from Bayer and Bellerophon, grants and personal fees for registry and data safety monitoring from Actelion, and was a consultant for end-point adjudication for Lung LLC, with fees paid to his employer (Intermountain Healthcare), outside the submitted work. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: R.C. Trembath has nothing to disclose. Conflict of interest: J.E. Loyd has nothing to disclose.

Figures

FIGURE 1
FIGURE 1
The history of genetic discovery in pulmonary arterial hypertension. WSPH: World Symposium on Pulmonary Hypertension.
FIGURE 2
FIGURE 2
From genes to therapies: precision medicine approaches in pulmonary arterial hypertension (PAH). BMP(R): bone morphogenetic protein (receptor); BRE: BMP-responsive element; CAV1: caveolin-1; FKBP12: 12-kDa FK506-binding protein. BMP signalling in endothelial cells is mediated by the ligands BMP9 and BMP10 via the ALK1/BMPR2 receptor complex. Endoglin serves as an accessory receptor. Signalling is mediated by phosphorylation of the receptor Smads (Smad1, 5 and 8), which then associate with Smad4 and translocate to the nucleus, regulating genes that contain BREs in their promoters. CAV1 facilitates receptor colocalisation, while KCNK3 encodes a potassium channel that contributes to pulmonary vascular tone. Genes that are mutated in heritable PAH are in bold. Potential therapeutic approaches targeted to these pathways include: exogenous administration of BMP9 ligand, increasing availability of functional BMPR2 receptors (hydroxychloroquine, etanercept), promoting readthrough of nonsense mutations to restore functional BMPR2 or Smad8 protein (ataluren), enhancing downstream signalling by relieving FKBP12 inhibition of BMP type 1 receptors (FK506), promoting CAV1-mediated receptor recruitment (elafin), or recovering KCNK3 channel conductance (ONO-RS-082).
See this image and copyright information in PMC

Comment in

  • doi: 10.1183/13993003.02148-2018

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