The Science

PVDOMICS is a study looking at different ways in which PH patients, those at increased risk for PH, and healthy controls are both similar and different. The study seeks to find currently unknown similarities and differences, including those that span multiple currently defined WHO groups of PH, which could add to our understanding of diagnosis and treatment of the disease. To find these similarities and differences, the study will analyze genetics, metabolites, proteins.

Genetics

Genetics testing involves analyzing your DNA. DNA is a chemical “code” that makes you unique and contains instructions for various functions in your body. This is called your “genome.” Your DNA is inherited from your mother and father and can be thought of as letters in a book. Your DNA is believed to consist of more than 3 billion of these “letters” (known as “base pairs”). Your body uses these to make three letter “words,” called amino acids, which together act to carry out body functions by making proteins. There are a total of 20 amino acids these three-letter base pairs can individually form.

Sometimes, for a number of different reasons, one of these letters will change from what is “normally” expected. This is called a “mutation” and each one of us has some. Having a genetic mutation does not necessarily mean there will be a noticeable change; some mutations cause subtle changes, but do not ultimately cause a change in body function; some changes are serious and can put one at higher risk for diseases like PH; some changes themselves are believed to directly cause disease.

For many years, genetic mutations in the “bone morphogenetic protein receptor type II” (BMPR2) have been linked to an increased risk in developing WHO Group 1 PH (PAH, pulmonary arterial hypertension). Additional genetic mutations are being identified both in PAH and other forms of PH (including ALK1, CAV1, EIF2AK4, ENG, KCNK3, and SMAD9). By performing genetic analyses on these 1,500 individuals, which will be kept without reference to the subjects’ identities, PVDOMICS hopes to discover new genetic mutations that could eventually aid in the in the diagnosis, risk prognostication, and treatment of the disease.

We believe that changes to your genetic code (or the exact “letters” contained in your DNA) are not the only component that contributes to heritable changes in PH. There are differences in items connected to your DNA (called “epigenetic modifications”) that can make the gene more or less likely to be seen by the body, and thus “expressed.”  In addition to looking at the genetic code, PVDOMICS will look at these epigenetic modifications to see whether differences correlate with how the disease progresses in different types of PH.

Proteins

Figure 1 – Central Dogma of Biology

Figure 1 – Central Dogma of Biology

The Central Dogma of Biology states that DNA is first turned into RNA (“ribonucleic acid”) through a process called “transcription.” This RNA can be considered a template for the machinery that produces proteins from the RNA, through a process called “translation.” Producing a template RNA conserves the DNA and reduces the risk of changes to this “template for the template.”
If the genome is considered what proteins ultimately could happen, the transcriptome can be considered what reasonably could happen (i.e., what templates are available for use to translate into proteins), and the proteome can be considered has happened (i.e., what proteins are produced and completing activities in your body). At any step along this process, there may be similarities and differences between PH patients, those at higher risk for PH, and healthy controls that provide a new understanding of the disease. PVDOMICS will analyze components of each of these processes for this updated understanding.

Blood Clotting

For decades, a question that has been asked is whether differences in blood clotting have a difference in how PH progresses and ultimate survival. Registries have analyzed whether treatment of certain types of PH patients with a commonly used anticoagulant has a positive impact on their survival, with mixed results. PVDOMICS will analyze information on your “coagulome” that will help to understand potential similarities and differences between and within PH groups as currently classified.

Images

Various types of images are frequently collected when physicians diagnose and classify PH. In addition to the genomic, transcriptomic, and proteomic information collected, which is largely unknown in this large of a patient cohort in the United States, PVDOMICS will also systemically collect information from images that are commonly used in the clinic.

  • Echocardiogram – An echocardiogram is done to look at your heart function. This is an ultrasound of your heart. It is done by a trained person holding a device (shaped like a microphone) on the skin of your chest with some pressure to look at the heart and surrounding large blood vessels.
  • Electrocardiogram – An ECG is a test that measures your heart’s electrical activity. You will be asked to lie flat on a table and several small electrode pads (like stickers) will be placed on your body. These electrodes record the beats of your heart.
  • CT Scan of Chest – A CT scan is a set of specialized x-rays of the lungs. This test provides information about the structure in general of your lungs, the tissue that makes up your lungs, and some insights into the large vessels in the lungs.
  • Cardiac Magnetic Resonance Imaging (MRI) – An MRI uses magnetic waves to take pictures of your heart. This procedure provides detailed pictures of the shape and function of your heart.
  • Ventilation/Perfusion (V/Q) Scan – This test provides images of which areas of your lungs are receiving air and compares them to images of your lungs showing which areas receive blood. This is a common screening test for WHO Group 4 PH (CTEPH, chronic thromboembolic pulmonary hypertension) which can show areas of the lungs that are receiving air normally, but not blood due to a chronic clot.

NHLBI Pulmonary Vascular Disease Phenomics Program


Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health with support from the Pulmonary Hypertension Association