Pulmonary Arterial Hypertension and Genetics: Interview With the Experts

Several genetic mutations have been implicated in PAH development. <i>Image credit: Gary D. Gaugler/Science Source</i>
Several genetic mutations have been implicated in PAH development. Image credit: Gary D. Gaugler/Science Source

In recent years, treatment advances have improved the survival rates of individuals with pulmonary arterial hypertension (PAH), a rare but devastating disease that affects an estimated 10 to 52 people per million.1,2 In addition, developments in genetics and genomics technology have begun to illuminate the mechanisms underlying the pathogenesis of PAH.

"Enormous progress has been made in recognizing the important contributions of genetics to most diseases, and PAH is among the diseases for which progress has been the most outstanding," according to James E. Loyd, MD, the Rudy W. Jacobson Professor of Medicine in the Division of Allergy, Pulmonary & Critical Care at Vanderbilt University School of Medicine in Nashville, Tennessee. "In the past, many diseases were believed to be idiopathic or primary, but progressively more of these are being recognized to have genetic origins, including PAH," he told Cardiology Advisor

In the most widely adopted classification scheme, PAH is divided into 3 types: heritable (HPAH, formerly called familial PAH), idiopathic (IPAH), and PAH linked with various systemic diseases or exposure to drugs or toxins.3 PAH research made great strides in 2000, when it was discovered that HPAH is most often caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene. "A defect in BMPR2 accounts for PAH in approximately 75% of families who have multiple PAH cases, and about 20% of idiopathic PAH for [which] other cases are not known in [the] family," said Dr Loyd.3,4

Since that time, mutations in related genes such as ALK1, ENG, and SMAD9 have also been identified, and researchers have found clues that could help elucidate genetic and epigenetic factors that modify the expression of the disease.3 "Pathophysiological changes occurring during the development of PAH are extremely complex and probably involve many genetic and epigenetic mechanisms that lead to changes in gene expression and proliferative and metabolic changes in cells," the authors of a 2013 review wrote.4

It is likely that "next-generation sequencing in selected families will identify new important genes for explaining heritable forms of PAH," which could potentially clarify disease mechanisms and novel treatment targets.4

To glean additional highlights regarding the current state of progress and future directions in PAH, Cardiology Advisor interviewed Dr Loyd and Wendy Chung, MD, PhD, the Kennedy Family Associate professor of pediatrics and medicine and director of clinical genetics at Columbia University in New York City. Both physicians have coauthored articles on the topic, including recent reviews published, respectively, in Circulation Research and the Journal of Pathology.1,3

Cardiology Advisor: What are some of the most significant findings regarding the role of genetics in PAH?

Dr Loyd: Remarkable improvements in sequencing and other technologies have made it easier to identify genetic variation in individuals and to understand its effect on the biology and pathogenetic mechanisms of the disease, with the goal of developing more effective therapy. Some of the most important findings relate to novel areas of genetics beyond the DNA coding sequence or epigenetic features, including the contributions of methylation, histone deacetylation, and micro-RNAs.3

Dr Chung: Beyond BMPR2, there are many different genes that can cause PAH, each of which is individually rare.

Cardiology Advisor: What types of genetic testing are available for PAH, and for whom is it most appropriate?

Dr Loyd: Clinical genetic testing for defects that have been associated with PAH are available, and these are most appropriate for patients with idiopathic or heritable PAH. Helpful information is available online at the Genetics Home Reference site5 by the National Institutes of Health or the Pulmonary Hypertension Association website (click on the "Consensus Statements" option under the "Medical Professionals" tab).6

Dr Chung: Genetic testing is appropriate for any patient with IPAH if they are interested in knowing the information for themselves or to predict risk for family members. This clinical testing is often covered by insurance. 

Cardiology Advisor: What should next steps be in terms of research in this area?

Dr Loyd: Many different research directions are underway around the country, with a focus on understanding the mechanisms and pathways by which genetic variation promotes disease. Most important, several teams are looking at how modification of the known pathways, or intervention with approved drugs, can be used to develop new therapies.1

Dr Chung: We need much larger samples sizes of patients to analyze and link with the clinical course, progression, and outcome.1 With larger sample sizes, we should be able to identify more of the genes causing PAH, understand how high the risk for FPAH is for mutation carriers, and determine response to treatment and prognosis by gene.

Cardiology Advisor: What else should our clinician audience know about the role of genetics in PAH?

Dr Loyd: All clinicians should know about the availability of genetic testing so they can direct patients and families to genetic counseling to optimize their health outcomes. When the genetic defect in a family is found, then it becomes possible for family members to better understand the risk to themselves and their progeny, and to avoid expensive screening testing when negative. In addition, family members who are considering childbearing should understand that it is now possible to prevent transmitting a serious genetic mutation to future generations.

Dr Chung: Many patients with idiopathic PAH have an underlying genetic cause, even without a family history of PAH, and this is especially true for children.1,4 


  1. Ma L, Chung WK. The role of genetics in pulmonary arterial hypertension. J Pathol. 2017;241(2):273-280. doi: 10.1002/path.4833
  2. Hoeper MM, Gibbs JSR. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev. 2014;23(134):450-457. doi: 10.1183/09059180.00007814
  3. Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115(1):189-202. doi: 10.1161/CIRCRESAHA.115.303404
  4. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D13-21. doi: 10.1016/j.jacc.2013.10.035
  5. Pulmonary Arterial Hypertension. National Institutes of Health; US National Library of Medicine. https://ghr.nlm.nih.gov/condition/pulmonary-arterial-hypertension. Published February 21, 2017. Accessed February 22, 2017.
  6. Consensus Statements. Pulmonary Hypertension Association. https://www.phassociation.org/MedicalProfessionals/ConsensusStatements. Accessed February 22, 2017.
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