Genetics and PH

PHA UK RESEARCH

In February 2020, the PHA UK conducted an online survey to ascertain what people with Pulmonary Arterial Hypertension (PAH) understand about the role of genetics in PAH, and to identify any information gaps. The survey was conducted in collaboration with Professor Nick Morrell, British Heart Foundation Professor of Cardiopulmonary Medicine at the University of Cambridge.

“We have known for some time that there is often a genetic cause for PAH, especially if more than one individual is affected in a family. This study is the first of its kind in a large patient population, and I’m delighted that the PHA UK has carried it out.”

– Professor Nick Morrell, British Heart Foundation Professor of Cardiopulmonary Medicine

NATIONAL COHORT STUDY OF IDIOPATHIC AND HERITABLE PULMONARY HYPERTENSION

Carmen Treacy, Research Study Coordinator for the National Cohort Study of I/HPAH, explains more about its aims and how healthcare professionals can get involved.  

Study aims

The National PAH Cohort Study was set up in 2013 to address some of the major unanswered questions in the field of PAH.

• What is the contribution of rare DNA variation in PAH?
• What are the environmental factors that trigger disease in bone morphogenetic protein receptor type 2 (BMPR2) mutation carriers?
• What is the true penetrance of disease in families with BMPR2 mutations?
• Are prognosis, clinical course and response to therapy determined by the molecular diagnosis?

Genetics of PAH

The most common gene associated with PAH is BMPR2, a member of the transforming growth factor-β (TGF- β) superfamilywhich was identified in 2000.  Up to 75% of cases of familial PAH occur due to BMPR2 mutations and also occur in up to 20% of apparently sporadic IPAH. Cases of familial PAH are inherited in an autosomal dominant manner with incomplete penetrance. The penetrance of PAH in BMPR2 mutation carriers is estimated to be 14% for men and 42% for women.  Although the presence of mutations in BMPR2 is the greatest risk factor for the development of PAH additional factors are required for disease manifestation. These may be genetic and/or environmental, though the identity of these factors remains largely unknown. Since 2000 more PAH risk genes have been identified due to technological advances in genetic sequencing enabling larger cohorts of patients to be sequenced but BMPR2 remains by far the most common gene involved.

Study set-up

The National Pulmonary Hypertension Centres of UK have established a research network to address these major questions in PAH. We aim to recruit as many newly diagnosed patients and relatives as possible until the end of 2022. We will look for additional mutations in genes using whole genome sequencing to identify a more complete understanding of the genetic contribution to PAH. Long term follow up of patients and their relatives will provide important information about how genetic mutations affect outcome and response to treatment. The information we learn will allow us to provide better estimates of risk of developing PAH to family members and identify new ways of treating this disease.

Each of the 9 designated centres in the UK have a dedicated research nurse recruiting and following up these patients. Clinical data is collected along with study bloods and an annual epidemiology questionnaire. Relatives of patients who are BMPR2 mutation carriers or have a family history of PAH are also invited to take part in the study to enable us to ascertain the true penetrance of the disease. They are followed up annually at their local PAH centres and have PAH screening tests such as bloods, echo and CPET’s.

Achievements

Since the study has started we have recruited over 740 patients and 74 relatives. Our study biobank now holds over 61000 samples for future research. This has been a huge achievement and we are very grateful to our study participants and the invaluable support we have received from the PHA-UK.

Future goals

Funding was initially received from the British Heart Foundation (BHF) and the Medical Research Council (MRC) to carry out the study. We now have further BHF funding in place until the end of 2022. This is mainly to cover the recruitment of relatives as this has been the most challenging part of the study. We hope over the next 2 years to recruit more relatives to help us understand the true penetrance of PAH and the trigger factors involved. As more is learnt about the genetic architecture of the disease treatment strategies may be revised to facilitate personalised medicine approaches resulting in better outcomes for patients.

How can you help?

We are keen to recruit as many relatives as possible over the next 2 years.

If you see a patient who is BMPR2 carrier or has a family history of PAH in clinic please contact the study nurse to see if they have been approached for the study

Further details can be found on our study website www.ipahcohort.com or please email us on cohortcoordination@medschl.cam.ac.uk