PH Research Corner: Genetics and inheritance of PAH


In this issue of the Research Corner, we will focus on the genetics and inheritance of Pulmonary Arterial Hypertension (PAH). 

According to the most recent world health organization clinical classification, PAH divides into 3 categories. It can be:

• idiopathic (with an unknown cause) 

• heritable (passed down in the family, previously known as familial) 

• associated (appears alongside another disorder). Genes functioning in an abnormal fashion can participate greatly in PAH. 

Can specific mutations lead to PAH? In 1997, scientists were able to locate mutations in a specific gene that was common in families that develop PAH. The gene, called BMPR2, is part of a larger signaling pathway that regulates survival and growth of endothelial cells (the cells lining the inside of the blood vessels). Further discoveries identified mutations in other members of the same signaling pathway in PAH patients. When these mutations are present, survival and function of the endothelial cells is compromised. This can eventually contribute to the development of PAH.   

As a PAH patient, do I have mutations in BMPR2 or its pathway? Genetic testing of PAH patients with either family history or unknown causes is currently a common practice. Around 70% of patients with a family history of PAH, classified as heritable PAH, will have mutations in BMPR2 or its pathway. Around 10-40% of PAH patients without family history (i.e. idiopathic PAH patients) can still be carriers of these mutations. In these cases, the disease is classified as “sporadic” PAH, which means they have a mutation but do not have a family history of PAH. In cases where PAH is heritable in a family, but patients do not have mutations in BMPR2 or its pathway, scientists conduct experiments to identify new mutations that could contribute to this condition. 

If I have mutations in BMPR2 or its pathway or if one/both of my parents have PAH, will I definitely develop PAH? Not necessarily. Only about 20% of individuals carrying these mutations will develop PAH. It is believed that these mutations alone are not sufficient to cause PAH, but a combination of genetic and environmental factors are needed. This phenomenon, when a patient caries a mutation but does not necessarily develop a disease, is referred to as “low penetrance”.  

If I am a carrier of these mutations, what should I do to keep myself from getting PAH? The presence of these mutations can make the lung more susceptible to development of pulmonary pathologies. There are some measures that can be taken to reduce the chance of development of PAH if you are a carrier. It is best to discuss these options with your pulmonary hypertension specialists who will be able to better tailor their answer to your specific needs and situation.  

Reference: Ma L and Chung WK (2014) The genetic basis of pulmonary arterial hypertension. Human Genetics 133(5):471-9.  

Please always keep in mind that while I can provide you with a small insight into PH research, you should always be able to get answers from your Pulmonary Hypertension Specialist, who is more familiar with your specific case and your treatment history. 

Contributed by: Mohamad Taha, B. Sc. PhD Candidate, Department of Cellular & Molecular MedicineFaculty of Medicine, University of Ottawa

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