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I'm Aware That I'm Rare: the phaware® podcast

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Vinicio de Jesus Perez, MD - phaware® interview 194

Oct 2, 2018

In this episode, Dr. Perez discusses genetic markers in a population of Iberian gypsies, who are afflicted with a very severe form of pulmonary hypertension that is called pulmonary veno-occlusive disease. Vinicio de Jesus Perez, MD is Assistant Professor of Medicine (Pulmonary and Critical Care Medicine) at the Stanford Adult PH Clinic where he trains fellows pursuing careers in PH and IPF. 

My name is Vinicio de Jesus Perez. I am an assistant professor in the Division of Pulmonary Critical Care Medicine at Stanford University. I'm also a staff physician in the Adult Pulmonary Hypertension Clinic, also at Stanford.

Today I would like to tell you a little bit about one of the ongoing projects that we are engaged in pulmonary hypertension, which has to do with elucidating genetic markers in a population of Iberian gypsies, who are afflicted with a very severe form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD).

This is a project that we're running in collaboration with colleagues in the Hospital Universitario la Paz in Madrid and the way this happened was that a couple of months ago, I received communication from a graduate student called Jair Tenorio, PhD who become interested after reading one of our publications on use of whole-exome sequencing to discover novel variants in patients with idiopathic pulmonary hypertension that we published around 2014.

He said, "Listen. We have this very interesting patient cohort. We have identified some patients that actually seem to have a familial form of this disease. All of these patients are the product of inter-family marriage. And we believe that there is some new genetic variants. We would like to start a collaboration where we can learn how to use next-generation sequencing strategies and validation tools to discover what the functional impact of these mutation might be."

Jair came to Stanford and stayed in our lab for three months where he had access to our genetic data and learned how to manipulate cell systems to study the effect of candidate mutations. Since returning back to Madrid, he has started do perform whole-exome sequencing of these patients and we have partnered with the U.K. Bridge cohort to collect information about patients with idiopathic and familial PVOD. The questions is: what makes this Iberian gypsy population unique? Are their genetic markers different from those that have been observed in other cohorts in Europe?   We have begun developing  an international consortium where members of our group will go to Madrid and interact with this Iberian gypsy population.  It is worth noting that, historically, this ethnic group has remained aloft due to fear of discrimination and distrust.  Luckily, the group in Madrid has established a bond of trust and have gained access to these families.   We will share our expertise in next-generation sequencing, bioinformatic strategies, and collaborate to identify what may be responsible for this aggressive phenotype.  Ultimately, I think we will obtain a better insight into what drives the development of PVOD from the genetic standpoint.

This is actually a tribe. We're talking about a tribe, we're talking about close to a hundred. And within that, different families. But again, I think it's hard to separate the families because there's been a lot of intermarriage. So, that part, it's a little bit hard. I haven't seen the pedigree analysis that they've done so far. They're going to be quite complicated, compared to what we're used to, when we follow families with heritable pulmonary hypertension.

A lot of these patients have already been seen at the hospitals. We know they actually have severe pulmonary hypertension. Blood samples have been collected, and that's going to be the source of the genetic material that we are going to be using. One interesting tidbit is that we're going to be using techniques to grow out endothelial cells that are circulating from their blood, and also we can potentially use pluripotent stem cell-based strategy to actually make endothelial cells or smooth out amongst the cells to use as a system to model what the pulmonary vasculature may be like. So if these patients have a particular genetic mutation, we could potentially use these cells to see how that affects the endothelium. This is something that has been used and demonstrated to be a feasible strategy by Dr. Marlene Rabinovitch and Dr. Joseph Wu

Historically, most patients with PVOD do really badly because the PH therapies don't really work as well. So what ends up happening is that patients may undergo transplant and at that time, we can capture the tissues and look at architecture, maybe even isolate the cells.

I think that this will also help us identify healthy carriers of mutations and follow them in time using echocardiogram and clinical visits.  Think about it: If we know that they are healthy at baseline and they develop PH with time, we may actually get some information about environmental factors or other modifiers that may be of interest in terms of understanding how genetic and environment play a role in developing PVOD.

Jair works with Pilar Escribano, who is the head of the PH group in Hospital Universitario La Paz. She is the clinician who follows these patients. Jair is a post-doc and he works on the genetics side. I think this is going to be really interesting.  We are just getting started but I think we have a really big opportunity to study a unique heritable form of pulmonary hypertension.

My name is Vinicio de Jesus Perez. And I am aware that I'm rare.

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