Active BRIDGE Studies - PAH

Pulmonary Arterial Hypertension (acronym PAH, project identifier B21) - This project will investigate the underlying genetic variation of idiopathic and heritable pulmonary arterial hypertension.

Prof. Nicholas Morrell

Prof. Nicholas Morrell

Pulmonary arterial hypertension (PAH) is a rare disease characterised by narrowing and obliteration of blood vessels in the lungs. Although PAH can occur at any age and affect both sexes, it occurs most commonly in young women, and manifests as worsening breathlessness on exertion. High blood pressure in the lungs eventually leads to heart failure and death. The BRIDGE-PAH study aims to elucidate major genetic factors contributing to this disease.

PAH is a devastating clinical condition that causes death within three years from diagnosis if left untreated. Although existing treatments can relieve symptoms, in most patients symptoms eventually progress, leading to disabling breathlessness even at rest. By this stage of the disease only lung transplantation can prolong life. There is an urgent need to develop new treatments based on a better understanding of the mechanisms underlying this disease. A genetic basis to PAH was first suggested by the observation that the disease occasionally occurred in families. In 2000 researchers identified mutations in a particular gene, called BMPR2, in the majority of these families. This discovery accelerated our understanding of the disease and has offered new avenues to develop treatments. It was subsequently found that mutations in BMPR2 also cause disease in patients with sporadic forms of the disease in whom there is no previous family history. Over the last few years additional uncommon mutations have been identified in PAH patients in genes that are related to the BMPR2 gene. Based on these observations it is likely that the majority of PAH is caused by genetic mutations, although additional environmental factors are often required for the disease to manifest. The BRIDGE-PAH study will recruit every patient in the UK with idiopathic or familial forms of PAH to undertake genetic sequencing of the coding regions of genes to attempt to elucidate the complete genetic basis of this disease. All patients in the UK are managed at one of seven National Pulmonary Hypertension Centres, where recruitment will occur. Additional patient samples will be available from collaborators in Europe. The discovery of the range of genetic mutations underlying PAH will provide a more complete picture of the cause of this disease and identify rational targets for new drugs. It will also pave the way towards prevention strategies for this disease and of the prediction of prognosis based on a genetic classification of PAH.