Is Pulmonary Hypertension a Genetic Disease?

Pulmonary arterial hypertension (PAH) is classified as idiopathic (IPAH), hereditary or associated with other conditions, such as connective tissue diseases, congenital heart disease, portal hypertension and exposure to drugs or toxins. When the disease is transmitted from parents to children, it is classified as Heritable Pulmonary Arterial Hypertension (HPAH). Regarding the genetic basis of PAH, the main gene involved is the bone morphogenetic receptor type II (BMPR2), located on chromosome 2q33. One of the great advances in this disease has been the knowledge of the genetic alterations that influence its development. More than 15 years ago, the most important gene was identified, BMPR2, and since then almost 400 mutations of this gene have been known.

Mutations in this gene have been identified in more than 80 percent of patients with HPAH, although only 20 percent of carriers eventually develop the disease. That means that the presence of mutations of the BMPR2 gene supposes a high increase of risk of suffering the PAH, but it does not imply with certainty that the patient is going to suffer the disease. On the other hand, the frequency of BMPR2 mutations in patients with IPAH is much lower, ranging between 6-40 percent. Given that they are mutations that are inherited in an autosomal dominant way (if a father has it and the child receives it, he can develop the disease); the genetic study is an option to discuss.

Approximately between 70 and 80 percent of patients with the familiar form of the disease, that is, with several members of the same family affected, are carriers of any of these mutations. However, between 15 and 25 percent of those who suffer from pulmonary arterial hypertension without known cause or family members who suffer from it (the so-called sporadic forms) are also carriers of some mutation. These data seem to indicate that a genetic study could help identify the possibility of developing PAH and diagnose it early, but this is a topic that still generates debate due to the ethical implications involved.

According to experts, conducting a genetic study, especially in childhood is very problematic because they can stigmatize the child with a disease that may not end up suffering in his life. That is why it should be analyzed very carefully with the parents, but always offering the possibility of carrying out this study.

The detection rate of some mutation of known genes is approximately 75 percent in HPAH, but the mutation deficit remains unexplained; even after careful molecular investigation of these genes in many cases no mutation is found. To identify other genetic variants predisposing to PAH, researchers have harnessed the power of next generation sequencing to successfully identify additional genes, which is adding new genes with potential impact on the development of this disease. In addition, common predisposing genetic factors for pulmonary arterial hypertension can be identified throughout the genome through association studies.

The availability of molecular genetics diagnostics has opened a new field for the care of patients, including genetic counseling for a serious illness, bearing in mind that the main predisposing gene has a very variable penetrance between families. The molecular information can be extracted from the genomic study of the tissues affected by PAH, in particular, from the tissues and pulmonary vascular cells, to obtain a vision of the mechanisms that lead to the development of the disease. High-throughput genomic techniques, based on next-generation sequencing, now allow quantifying and accurately analyzing ribonucleic acid and different species of these RNAs, including ribonucleic micro-acids. This is a promising path in which experts are working since it allows a genomic-scale investigation of epigenetic or regulatory mechanisms that include methylation of deoxyribonucleic acid, methylation of histones and acetylation, or binding to the transcription factor.

According to the researchers, although the consequences of the disease were known, very little was known about what caused this condition in some of these patients.

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