Scientists publish first complete record of genetic mutations behind rare vascular disease

Human anatomy - heart

The genetic architecture of a debilitating and potentially fatal vascular disease has for the first time been detailed in its entirety, providing clinicians with the comprehensive data needed to improve diagnosis and deliver more personalised patient care.

Scientists investigating Pulmonary Arterial Hypertension (PAH) have compiled the most up to date and complete record of all the defective variations found in the genes that cause the disease.

The new study, led by Dr Rajiv Machado from the University of Lincoln, UK, draws together the complete genetic information of hundreds of individuals affected by PAH. This advance will not only offer new opportunities to identify the mutation which causes PAH in individual patients but will also provide an important tool to correlate genetic data, allowing for more tailored approaches to the clinical management of the disease. It has been published in the online academic journal Human Mutation.

PAH is an often fatal disorder resulting from several causes, including an assortment of genetic defects. It is a progressive disease characterised by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Symptoms are shortness of breath, dizziness, swelling (oedema) of the ankles or legs, chest pain and a racing pulse.

Heritable PAH leads to a chronic elevation of pulmonary arterial pressure, which can result in heart failure.

While mutations in a gene called BMPR2 are the single most common cause for hereditary cases, mutations capable of causing disease have been observed in approximately 25 per cent of patients without a prior family history of disease.

The new study, which brings together data from specialist PAH centres based in Germany, France, North America and the UK,  describes molecular genetic analyses of the 10 functionally characterised genes that cause PAH and provides a compilation of all mutations identified to date.

It also describes an additional 370 independent mutations of BMPR2 in patients, either previously excluded from or identified since the last comprehensive mutation update by Dr Machado and colleagues in 2009. Of these, 81 are new variations.

Dr Machado, from the University of Lincoln’s School of Life Sciences, said: “This is the most comprehensive and complete compilation of all defective variations in the genetic risk factors for PAH. This will allow the clinical geneticists, with a greater degree of certainty, to conclude that the gene variations present in a patient are either disease causing or of unknown significance. This could inform a patient’s decisions about starting a family or undertaking pre-natal testing. Prior to this a clinician would have to try and understand genetic data received for a single patient by trawling through historic manuscripts to make a diagnosis. This report has the potential to be of great importance to the diagnostic centres around the world.

“The continuing identification of genetic factors, as explored in this paper, provides unique insight to the genetic mechanisms driving disorders of pulmonary vascular function. These data provide a key resource in data interpretation and how these genetic insights may lead to the potential discovery and delivery of novel targeted therapeutic options in PAH.”

This important resource of clinical and scientific data has now been posted on a freely available public repository, namely ClinVar, and will be accessible through Dr Machado’s Lincoln profile page.

The emergence of next-generation sequencing (NGS) allows scientists to sequence much more quickly and cheaply, and as such has revolutionised the study of genomics and molecular biology. NGS has allowed researchers to identify novel, rare genetic variations in the PAH disease spectrum, detailed in this study. It is likely that future avenues will include the use of more NGS technologies, the pinnacle of which is whole-genome sequencing – a process that determines the complete DNA sequence of an organism’s genome at a single time.

Lincoln researcher to join prominent scientific debate

A leading cardiovascular disease researcher from the University of Lincoln, UK, has been invited to take part in a debate comprising top thinkers from science, medicine, health, economics, government and the media.

Dr Rajiv Machado, from the School of Life Sciences, is one of a group of prominent scientists invited to join the audience for the Astellas Innovation Debate 2015 at the Royal Institution of Great Britain in London.

Dr Machado is an eminent voice in the fight against Pulmonary Hypertension and has published breakthrough research into the causes of this debilitating vascular disease.

The debate brings together some of the world’s most progressive thinkers to discuss the role of innovation in solving the greatest challenges of our time. Past panellists have included Nobel Laureates Professor Sir Andre Geim and Dr Elizabeth Blackburn, Lord Robert Winston, Baroness Sally Greengross and Professor Brian Cox.

This year’s debate entitled ‘I-Genes: What the DNA and Data Revolutions Mean for our Health’, chaired by Jonathan Dimbleby, will explore whether science and technology can deliver truly personalised healthcare for all. George Freeman MP, Minister for Life Sciences, will give the keynote speech.

With the price of DNA sequencing plummeting, and the increasing ‘smartness’ of handheld electronics and point-of-care diagnostics, the prospect of personalised medicine fine-tuned to a patient’s genetic make-up no longer seems a far-off dream. Already health apps are giving the public unprecedented opportunities to monitor and manage their own fitness; in the future, we are promised, technology and genomics will combine to utterly change the patient’s experience.

As major projects like the UK government’s 100,000 Genome Project gear up to provide the fundamental medical science this future will need, the panel of world-leading experts will debate just what differences this new era of personalised healthcare will deliver.

The Innovation Debate 2015, which takes place at 6.30pm on Thursday, 29th January, will be broadcast live through and

Research breakthroughs advance understanding of genetic causes of vascular disease

The world’s leading voices in the fight against Pulmonary Hypertension have compiled a special publication detailing the breakthrough research into the causes of this debilitating vascular disease.

Co-author Dr Rajiv Machado, from the School of Life Sciences, University of Lincoln, UK, attended the World Symposium on Pulmonary Hypertension in 2013 as an invited member of the symposium’s genetics and genomics task-force.

Papers arising from this conference, which brought together the most respected clinicians and scientists in the field, have now been compiled in a special edition of Journal of the American College of Cardiology.

The symposium, which discussed several forms of resistance in lung vessels including those associated with common disorders such as congenital heart disease and HIV, resulted in a powerful consensus around key issues and recommendations.

The replication and extension of these studies should serve to further define the genetic landscape surrounding vascular disease.

Dr Machado said: The aim of the symposium was to report new information and how this could then be translated into clinical medicine by providing novel targets for therapy. The results have now been published as the definitive scientific consensus on this area of disease.”

Dr Machado’s main research focusses on Pulmonary Arterial Hypertension (PAH), a progressive disorder characterised by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs.

Symptoms include shortness of breath, dizziness, swelling (oedema) of the ankles or legs, chest pain and a racing pulse.

Dr Machado was part of a team that discovered the primary gene that causes PAH and has since gone on to investigate the disease pathway, isolating more contributory genetic mutations.

As reported at the symposium, Dr Machado’s investigation of 300 patients with disparate forms of PAH – the largest study of its kind – resulted in the identification of three novel genes which appear to cause pulmonary dysfunction.

A process called next generation sequencing (NGS) was used to exclude the likelihood of the observed genetic variation being present in the general population.

In a separate study, colleagues reported two additional genetic causes of disease present only in PAH patients and, intriguingly, a genetic variant enriched among patients but present in all of us.

Dr Machado said taken together the findings presented promising new avenues for research.

“It is extremely rare to find this form of variation in a disease like this,” he said. “Identification of this alteration may provide a new target for PAH treatment. It has wide ranging significance to our understanding of lung disease. It all contributes to the genetic architecture of the disease and our understanding of what causes it.”

Dr Machado is now working on population-specific genetic patterns, looking at two subsets of PAH, including an Indian group which has no family history of the disease. He will use next generation sequencing to drive a baseline genetic profile of this previously unstudied population.

Dr Machado will also carry out full DNA sequencing to interrogate the causes of childhood PAH, a particularly severe form of disease which is currently not well understood.

The full paper ‘Genetics and genomics of pulmonary hypertension’ can be viewed at