PVDOMICS and What It Means for the PH Community

Since 2000, PHA has created five distinct research programs through which we have committed almost $16,000,000. Each year, through those programs, we support about a dozen research projects. Each year, through our partnerships, our donors' research dollars are doubled.  

PHA's most recent research partnership - our second with NIH - will help expand a new program that is generating more excitement among researchers than anything we've seen before. PHA's $500,000 commitment, while adding 2 percent to the overall budget, is allowing the program to expand by 20 percent. We feel that's a great investment!

This week, I'm pleased to introduce PHA's Senior Director of Medical Services, Michael Gray, as our guest blogger. He explains the new PVDOMICS program and what it means to the PH community.  

As I turn this page over to Michael, I should tell you that PH is the first disease that will be studied in this way. NIH has told us we are preceding the diseases that will follow because of the strength and structure of the PH community. As part of this community, you are making this important advance possible.

"The only simple truth is that there is nothing simple in this complex universe. Everything relates. Everything connects"
-Johnny Rich, The Human Script

For centuries, scientists have been fascinated with how traits are passed from one generation to another. Significant progress has been made in this understanding, from Gregor Mendel’s discovery of the laws of inheritance with pea plants in the mid-nineteenth century to Dr. Marshall Nirenberg decoding the language of DNA at the National Institutes of Health (NIH) in the mid-twentieth century. Despite our increased understanding, we still have not solved how genes and changes to your genetic code called “mutations” affect most diseases, including pulmonary hypertension. A new initiative through the NIH, the “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program, seeks to change that for this particularly devastating disease state.

Mutations, or accidental changes in the DNA code, can occur frequently as cells duplicate, and can even be passed onto the next generation when this mutation occurs in a sperm or egg cell. Mutations sometimes will cause no changes to the individual, sometimes will cause harm to the individual, and sometimes can even provide a benefit. Genetic changes like this have been directly implicated in a number of diseases, including cystic fibrosis, sickle cell anemia, Tay-Sachs disease, and phenylketonuria. Genetic changes have also been implicated in PH, most famously with the discovery of the “bone morphogenetic protein receptor, type II” (BMPR2) gene. However, we don’t know exactly how changes in the BMPR2 “code” lead to PH. We know that BMPR2 genetic mutations are present in more than 70 percent of people with hereditary PAH and 25 percent of people with idiopathic PAH; but having the genetic mutation does not mean you eventually have PAH.

Think of DNA like letters in a book. Individually, these letters have no meaning; together, they tell the story that makes you, you. This story can be changed in a number of ways. Certainly letters and even entire words can be added, removed or changed, which might or might not change the meaning of the story. But direct changes to the letters on the page is only one modification that can have an impact on how you read the story. Maybe your book has a sentence that has been highlighted, or bolded; the words and the meaning of this sentence have not actually changed with this modification, but it has been emphasized in a way that has consequences in context. Maybe your book has a stain on one of the pages masking several words; the words are still there, but hiding these words could change the entire meaning. These different types of changes to how the “story” of your DNA is told make up a web of interactions that can have consequences nearly as drastic as finding one disease causing “gene.” This web includes the molecules that take chapters of your DNA “story” from the nucleus to your entire cell (called RNA), the proteins that are made by this RNA and used by your entire body, and how your cell uses energy to name just three strands of this web.

The NIH in Bethesda, Md., is the world’s largest biomedical research institute, with more than 5,000 scientists working on a number of scientific advancements with basic scientists, physician scientists, patient advocacy organizations, pharmaceutical companies and, of course, patients and family members themselves. The NIH has a long history working in pulmonary hypertension, beginning more than 35 years ago with an early, important registry characterizing the devastating nature of PAH. Since then—with significant advances in the field including 12 PAH-targeted therapies, a successful surgical therapy for CTEPH, and a medical therapy for a specific form of CTEPH—the NIH continues to invest in successful PH research. The most recent demonstration of this is the PVDOMICS program.

PVDOMICS seeks to ask research questions about PH in a way that will lead to a better, more complete understanding of the disease and to developing therapeutics that are more precise by building a clinical research network of seven centers across the United States. They will be performing a comprehensive analysis on around 1,500 patients with all types of PH (WHO Groups 1-5), collecting a range of clinical information; blood for analysis of genetics and the molecules that turn on and off expression of these genes; and imaging studies normally used in the clinic to better understand the difference between normal and diseased lung vascular tissue. There are many benefits from analyzing these very different types of information together, according to the NIH. If the investigators are able to develop this robust, more complete understanding of why some people develop PH and others with similar risk factors do not, more sensitive measures of diagnosis, more uniform responses to medications, and new biomarkers of disease worsening could be discovered. It is anticipated that most WHO Group 1-5 pulmonary hypertension patients who want to participate in this research study may be able to enroll.

The Pulmonary Hypertension Association is a proud partner with the NIH in this important study, and in 2014 awarded a five-year grant of $500,000 to the program to support one of the clinical centers in collecting data from 250-300 patients. For more information on the PVDOMICS program, please see the Pathlight article on PVDOMICS from the winter 2015 issue.