Vascular and Matrix Genetics

The Laboratory of Vascular and Matrix Genetics is led by Dr. Beth Kozel. As a matrix biologist, vascular biologist, and geneticist, Dr. Kozel seeks to better understand the factors that influence vascular disease severity in patients with rare connective tissue disorders.

Beth Kozel, M.D., Ph.D.

Senior Investigator Research Interests

Research Interests

As a matrix biologist, vascular biologist, and geneticist, Dr. Kozel seeks to better understand the factors that influence vascular disease severity in patients with rare disorders. The majority of Dr. Kozel’s work focuses on the study of two elastin insufficiency-related diseases: the neurodevelopmental condition known as Williams syndrome (WS) and isolated supravalvular aortic stenosis (SVAS), a narrowing of the aorta, the vessel that carries blood from the heart to the rest of the body.

As its name implies, elastin is an elastic protein — it helps blood vessels as well as other tissues in the body stretch and recoil. Individuals with WS are missing one copy of 25-27 coding genes, including the elastin gene — usually there are two copies of each of these genes. Those with elastin-associated SVAS have genetic changes affecting only elastin. With only one good copy of the elastin gene, persons with WS and SVAS make inadequate quantities of elastin, which predisposes them to stiff blood vessels that are prone to stenosis (or vessel narrowing), restricting blood flow. While some patients with WS (up to 35 percent) have no appreciable vascular abnormalities, approximately 20 percent of affected people have severe artery disease requiring surgical intervention to correct areas of stenosis. Patients in the middle of these two extremes of WS have moderate vascular problems.

The variability of the clinical signs of WS suggests that other genes work with the elastin gene in determining disease severity. To investigate this, Dr. Kozel initially began her work by studying mice with less elastin and looking to find additional gene changes throughout the genome (modifiers) that were associated with blood pressure and blood vessel size differences. Those studies led to the finding that changes in the levels of oxidative stress genes could influence the risk of hypertension in this group —and that medications aimed at reducing reactive oxygen species (antioxidants) could positively impact blood pressure and vessel stiffness.

More recently, Dr. Kozel’s team has started to look at changes in DNA patterns in people with WS. Together with collaborators worldwide who enabled a growing collection of more than 500 DNA samples from people with WS, the Laboratory of Matrix and Vascular Genetics has found that certain variations in extracellular matrix and immune genes influence the risk of severe narrowing of the blood vessels in people with WS. Initial studies were done by surveying the protein coding part of the genome, but more recent efforts have turned to non-coding and epigenetic variation. Non-coding and epigenetic variation are important for influencing when and where a gene is turned on—and are understudied sources of disease variability. Engaging families with atypical changes to the DNA in the WS region (including those with SVAS for whom no gene change has been found) has allowed the team to understand the role of the various genes in the WS region better. Induced pluripotent stem cells made from participants’ blood cells have enabled us to study a patient’s blood vessel cells without needing to access the blood vessel itself.

In addition to her genetic studies, Dr. Kozel’s group also brings in patients with WS for deep phenotyping studies at the NIH Clinical Center. There, her team’s primary emphasis in the Heart, Lung, and Blood institute is on cardiovascular health and her recent work has shown differences in blood vessel stiffness and heart rate variability in WS. Together with known problems with stenosis and tortuosity, these features may contribute to the increased risk of sudden death seen in WS and elastin-associated SVAS. In addition to the cardiovascular studies, her group has collaborated with expert clinicians and scientists in several NIH institutes to investigate lung, eye, developmental, and gastrointestinal symptoms in this population. By combining those findings using machine learning, they are starting to identify important patterns in health outcomes. Knowledge of those patterns can help deliver better care to patients because health concerns may be identified before they become problems.

More recently, Dr. Kozel’s team and their collaborators at Geisinger Health System were awarded a U01 grant to take a completely different approach to genetics. Instead of starting with a group of people with shared symptoms and giving them a diagnosis, they are using an innovative gene first approach to identify a group of people with gene changes in connective tissue genes and then looking to find what they have in common. Initial investigation is done by medical record review at Geisinger and then participants are invited to come to the NIH for full assessment. Those studies are ongoing but have already uncovered new and important health findings for people with changes in the ELN and LOX genes.

Clinical Trials and Studies

Recruiting
All Ages
All Genders
Not Accepting Healthy Volunteers
Do you or your child have Williams-Beuren syndrome (WS) or Supravalvular Aortic Stenosis (SVAS)? Symptoms of both conditions include vascular problems that can be mild or serious. Researchers want to find out why only some people with WS and SVAS have serious symptoms while others do not. Participants in this study will provide blood or saliva samples to help researchers see what DNA or environmental changes affect the severity of the disease. This study is located at the NIH Clinical Center in Bethesda, Maryland.
Recruiting
All Ages
All Genders
Accepting Healthy Volunteers
Do you or your child have Williams Syndrome (WS) or supravalvular aortic stenosis (SVAS) or are you interested in helping research on these conditions? The blood vessels in people with WS or SVAS have less elasticity, which can cause them to narrow. This study aims to see how blood vessel differences in people with these conditions affect organs in the body including the heart, gut, kidneys, and brain. This study is open to people with one of these conditions or healthy volunteers between 3 and 85 years old. The study takes place at the NIH Clinical Center in Bethesda,
Recruiting
All Ages
All Genders
Not Accepting Healthy Volunteers
Have you had a genetic test that revealed a change (mutation) in the genes that affect your body's elastic fibers? This study aims to learn more about the impact of changes in connective tissue genes on an individual's overall health. To participate in this study, you or your child must be between the ages of 2 and 100 years old. You must have also had a genetic test that identified changes in a gene that affects elastic fibers (e.g., ELN, LOX, MFAP4, FBLN5 and EFEMP). This study is located at the NIH Clinical Center in Bethesda, Maryland.

Meet the Team

Beth Kozel, M.D., Ph.D.

Beth Kozel, M.D., Ph.D.

Lasker Clinical Research Scholar

Dr. Beth A. Kozel graduated summa cum laude from Washington University in St. Louis with a bachelor’s degree in biochemistry in 1996. She attained a medical doctorate and doctorate in cell biology and physiology at the Washington University School of Medicine (WUSM) in 2004 through a combined M.D.-Ph.D. program. Dr. Kozel completed her residency in pediatrics at St. Louis Children’s Hospital and her residency in clinical genetics at WUSM. She began her academic career at WUSM before moving to the NIH in 2015 as a Lasker Clinical Research Scholar. Over the years, she has received numerous awards for research, clinical care, and mentoring, including the NHLBI Director’s Award for Innovation in 2021 and the Williams Syndrome Association’s Hope award in 2019. Dr. Kozel has authored or contributed to more than 70 publications and is a member of several professional societies including the American Society of Matrix Biology and the North American Vascular Biology Organization and is a Fellow of the American College of Medical Genetics and Genomics.

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Joy Freeman, RN, BSN

Research Nurse
Sharon Osgood, MS, RN

Sharon Osgood, MS, RN

Research Nurse
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Neelam Raja, NP

Nurse Practitioner
Daniel Chertow

Daniel Chertow

Pre-doc IRTA
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Grace Ge

Pre-doc IRTA
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Elahe Hasanzadeh

Research Fellow
Teresa Luperchio, Ph.D.

Teresa Luperchio, Ph.D.

Research Fellow
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Likitha Nimmagadda

Pre-doc IRTA
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Sara Procknow

Special Volunteer
Emily Ruiz Escobar

Emily Ruiz Escobar

Pre-doc IRTA
Claudia Gomez

Claudia Gomez

Patient Care Coordinator
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Zhanna ter Poghosova

Data Manager
lab members

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