Faculty Spotlight: Amy Erica Lin, MD, PhD
Investigating a New Risk Factor for Heart Disease
Scientists have known for decades that high blood pressure, high cholesterol, smoking and obesity are risk factors for heart disease. But less than a decade ago, researchers discovered a significant new risk factor called clonal hematopoiesis of indeterminant potential (CHIP). Caused by genetic mutations acquired after birth in stem cells that produce blood cells, CHIP becomes more common with age. These CHIP mutations increase the chances of developing cardiovascular disease by up to 40 percent – even in patients who appear to be otherwise healthy.
Amy E. Lin, MD, PhD, who recently joined the UCSF Cardiology faculty, is an expert in CHIP, leading efforts to find out more about its causes and possible therapeutics.
Some of Dr. Lin’s mentors helped discover CHIP, which has a complex backstory. During our lifetime, our bodies naturally accumulate mutations in our cells as they divide. The most rapidly proliferating group are our hematopoietic stem cells. These are precursor cells that give rise to every type of blood cell – including white blood cells, immune cells, and red blood cells – through a process called hematopoiesis. These genetic mutations are a normal part of aging, and most mutations don’t meaningfully affect cell function.
However, some genetic mutations provide stem cells with a proliferative and survival advantage, turbocharging their ability to grow and divide through a process called clonal expansion. It’s estimated that there are somewhere between 50,000 and 200,000 hematopoietic stem cells in adults, but with clonal expansion, blood cells derived from a single one of these stem cells make up an outsized, measurable percentage of the body’s blood cells. “The prevalence of CHIP increases with age, and affects 10 to 20 percent of people age 70 and older,” said Dr. Lin.
Her mentors discovered that certain CHIP mutations increased individuals’ risk for developing a blood cancer such as leukemia by about 2 percent per year. But they also found that these patients’ overall risk of developing cardiovascular disease doubled or even quadrupled, depending on which gene mutation they had. “These are blood cells that affect the heart,” said Dr. Lin. “We know that our immune cells and inflammatory processes play a big role in cardiovascular disease and atherosclerosis, so it’s very interesting to have this connection between hematopoiesis, a precancerous stage, and also cardiovascular disease.”
Studies conducted by Dr. Lin and others have suggested that patients with CHIP may be at increased risk for diseases such as heart failure, aortic stenosis, peripheral artery disease, cardiac arrhythmias such as atrial fibrillation, inappropriate blood clotting, and perhaps also pulmonary hypertension.
Most patients with a CHIP mutation do not progress to developing cancer. Those that do likely experience a “second hit” – another acquired mutation that predisposes them to cancer. UCSF’s Precursor Hematology Clinic already monitors patients with CHIP, offering them the opportunity to enroll in clinical trials to investigate ways to reduce their risk of developing cancer. “My goal is to build something similar on the cardiovascular side, looking at individuals with CHIP and determining how to reduce their risk for cardiovascular disease,” said Dr. Lin.
Discovering More about CHIP
To do that, Dr. Lin recently established the CHIP-Cardiovascular Disease (CHIP-CVD) Clinic, which collaborates closely with the Precursor Hematology Clinic and is based within the UCSF Section of Cardio-Oncology and Immunology. In addition to following patients with CHIP over a number of years, she is also launching the CHIP, cARdiovascular dIsease and OuTcomes (CHARIOT) registry and biobank, which will provide tailored screening and cardiovascular care for patients with CHIP mutations.
“We want to determine the prevalence of CHIP, and learn more about its natural history and outcomes,” said Dr. Lin. “We also hope to tease out patients’ risk if they don’t have any known cardiovascular disease, and identify genes and pathways involved in pathogenesis of CHIP.”
The registry will examine a patient’s CHIP status at the time they join the registry, and collect additional samples over time to learn whether the size of their clonal population remains the same or expands. Dr. Lin and her colleagues will also study whether patients acquire additional CHIP mutations, and how this might correlate with their cardiovascular disease, cancer state, or other inflammatory disorders.
“We also hope to find novel, targeted therapeutics that could reduce CHIP-associated risk,” said Dr. Lin. So far, there are no FDA-approved interventions for CHIP in either the hematology or cardiovascular space, though there have been some promising advances. For example, in 2017 the CANTOS Trial studied whether repurposing an anti-inflammatory medication already approved to treat some rheumatological diseases could reduce risk of heart attack or stroke in patients with atherosclerosis. It targeted the IL-1β inflammatory pathway and did significantly reduce the rate of cardiovascular events. However, the FDA did not approve its use to prevent cardiovascular disease because it increased risk of serious infection.
Interestingly, a substudy later revealed that participants who had CHIP mutations in the TET2 gene responded better to this IL-1β antibody, compared with participants without CHIP. “That demonstrates a potential for therapeutics, and targeting inflammation is a good first step for looking at how we would target CHIP for individuals with cardiovascular disease,” said Dr. Lin.
Not all CHIP is created equal: the amount and type of mutation appears to influence risk. The definition of a CHIP mutation is that a patient is otherwise healthy, and their variant allele frequence (VAF), or percentage of a single type of mutant cell, represents at least 2 percent of all blood cells. “Smaller VAFs have a lower risk,” said Dr. Lin. “For example, a group that studied CHIP in heart failure showed that although individuals with lower than 2 percent VAF did not have a statistically significant increase in risk, their risk was still higher than individuals without CHIP. We’ve noticed from a number of different large cohort studies that patients with a large VAF have an increased risk of developing cardiovascular disease, heart failure, atherosclerosis and atrial fibrillation. However, we don’t yet know if reducing VAF size reduces risk of developing cardiovascular disease.”
Also, there is not just one type of CHIP mutation. Instead, researchers have identified a handful of CHIP mutations, such as TET2, DNMT3A, ASXL1, and JAK2, that may affect individuals through different pathways. Dr. Lin hopes to collaborate with other CHIP biobanks across the country to study specific gene mutations of interest.
She has previously conducted a number of studies using data from the UK Biobank, which has 500,000 participants and a rich trove of de-identified clinical information and biospecimens. However, the vast majority of that biobank’s participants are of European ancestry, which can limit generalizability. “One of the strengths of our biobank is that we will be able to look at diverse populations and their CHIP status over time,” said Dr. Lin.
Another important aim is learning more about patients’ baseline knowledge about CHIP, and how they might want to proceed. “Many of my patients have already seen a hematologist and discussed CHIP with them, so they have received some pre-education and are often very savvy about genetic testing,” said Dr. Lin. “We want to get a sense of their understanding of how CHIP affects risk of cardiovascular disease, and whether they would want to be sequenced for CHIP. That will help guide us in how we use CHIP as a biomarker.”
An Unconventional Path
Born in Toronto, Dr. Lin earned her bachelor’s degree in immunology from the University of Toronto, where she went on to complete her medical degree. She also earned a PhD in medical biophysics, working in the lab of Tak Mak, PhD, a pioneering immunologist and cancer researcher who discovered the T cell receptor.
“I thought I was going to become an oncologist, and I really loved cancer biology, pathways, and targeted therapies that were being introduced at that time,” said Dr. Lin. She focused on novel therapeutics to target cancer treatment, studying protein degradation and an E3 ligase that was important in NF-κB regulation, which plays a critical role in regulating inflammation.
However, when she completed her PhD and went on to her internal medicine residency at the University of Toronto, she realized that she was even more intrigued by cardiology. “I love the pathophysiology, the amount of patient-centric care, and the preventive element of cardiology,” said Dr. Lin. “Then I discovered cardio-oncology, which was very new at the time, and thought, ‘This is perfect!’”
Cardio-oncology is an emerging subspecialty which focuses on the cardiovascular health of cancer patients and survivors. By learning more about the mechanisms by which cancer therapies can damage the heart, cardio-oncologists also seek to illuminate the biology of more common forms of heart disease, such as atherosclerosis and heart failure.
“I saw the connection between the oncology and cardiovascular disease worlds,” said Dr. Lin. “The majority of cancer treatments now are so good that patients survive their cancer, but end up developing cardiovascular disease, which is their greatest mortality risk in the survivor years. There is a great opportunity to learn more about shared mechanisms and pathways that can affect both cardiovascular disease and oncologic processes. After completing my internal medicine residency, I realized that to get the full breadth of training in cardio-oncology, the best place was the Brigham, so I set my sights there.”
At Brigham and Women’s Hospital in Boston, one of her main mentors for cardiology fellowship was Peter Libby, MD, a pillar in the field of cardiovascular disease inflammation, as well as scientific leader on the CANTOS Trial and a coauthor of the original paper linking CHIP with atherosclerotic cardiovascular disease. “He’s a great human and mentor, very supportive as well as brilliant,” said Dr. Lin. Her other primary mentor was Benjamin Ebert, MD, PhD, a hematologist who now leads the Dana-Farber Cancer Institute and was the senior author of the first paper on CHIP.
“Both Ben and Peter created opportunities for people, were supportive in whatever way they could be, and nurtured my passions,” said Dr. Lin. “I’ve had a very unconventional path to where I am now, and that was only possible because I had mentors who allowed me to explore my interests and showed me opportunities. Their response to my questions was, ‘No, it’s not crazy. Yes, it can be done, and we can help you.’”
During her fellowship, she conducted lab research showing that the TET2 CHIP mutation increased risk of developing atrial fibrillation through activation of the Nlrp3 inflammatory pathway, and contributed to a UK Biobank analysis suggesting that CHIP may be a novel risk factor for cardiac arrhythmias. She also coauthored review articles about the intersection of CHIP with aging, cardiovascular disease and cancer, as well as CHIP’s possible role in both malignant and nonmalignant diseases.
From Biotech to Academia
After completing her fellowship in 2022, Dr. Lin moved to the Bay Area to become the medical director of TenSixteen Bio, a biotech startup focused in part on using CHIP to treat age-related diseases. “They were working to develop new therapeutics for individuals with CHIP and cardiovascular disease, and it was a great opportunity,” said Dr. Lin. “I had always wondered what made a good therapeutic, and how do you bring that to the population? We did a lot of really good work and tried to advance that space.”
After spending all her training in academic research and clinical settings, Dr. Lin learned a lot about the challenges of translating a finding from academia to something clinically useful. “It takes a lot of effort, and there are many steps,” she said. “I learned that in a pharma or industry setting, they are always looking a few steps ahead. What are the hurdles to developing CHIP sequencing, then integrating that into trials? What are the costs for developing these tools and conducting trials? It was good to see that industry sees potential in CHIP, in both the cardiovascular disease and oncology spaces.”
When she moved to the Bay Area, she reached out to a longtime colleague, Javid Moslehi, MD, founding chief of the UCSF Division of Cardiology’s Section of Cardio-Oncology and Immunology and the William Grossman, MD Distinguished Professor in Cardiology. Dr. Moslehi is a world expert in cardio-oncology and immunology, and has been at the forefront of the field since its early years. “I told Dr. Moslehi that I was moving to California for this job, and mentioned that I was sad to be giving up my clinic,” recalled Dr. Lin. “He said, ‘You can have a volunteer clinic at UCSF.’”
So twice a month, she held a half-day CHIP clinic. “That started my connection with UCSF,” said Dr. Lin. “There’s an advantage for UCSF to gain insights of people who are in biotech, and it also allowed someone like me to maintain that patient interaction. A lot of my questions come from my work in the clinic. That whole academic-industry relationship is really strong at UCSF. It’s a great institution of really outstanding, clinically focused people, combined with a strong push for research and a robust tie with industry, which makes UCSF a unique place.”
While she enjoyed her work at TenSixteen Bio, she missed the collaborative environment of an academic institution. In 2023 she was recruited as a full-time faculty member within the UCSF Division of Cardiology. “Now I get to collaborate with the Division of Hematology/Oncology as well as the Cardiovascular Genetics Program,” said Dr. Lin. “I’m looking forward to working across disciplines to answer questions such as how to develop CHIP testing, as well as investigating the specific mechanisms of how CHIP mutations give rise to proliferative advantage or an inflammatory state.”
“Dr. Lin has been a terrific addition to our Section of Cardio-Oncology and Immunology,” said Dr. Moslehi. “Her expertise and passion for CHIP will help build an important new dimension to our clinical and research programs.”
‘We Have a Plan’
Dr. Lin is very happy to be able to be a physician-scientist at UCSF. “I like interacting with patients and explaining things to them,” she said. “Being on the receiving end of medical care can be scary. With cardio-oncology, patients are already dealing with a cancer diagnosis and chemotherapy. If they also have a cardiovascular issue that bars them from going forward with their chemotherapy, I like being the person who tells them, ‘It’s okay – we have a plan, and we can get through this.’ Our cardio-oncology and immunology group provides support to patients during cancer treatment, in their survivorship years, and now I’m hoping to build support in their precursor, healthy stage as well.”
She also enjoys mentoring trainees who are interested to learn more about cardio-oncology in both the clinical and research settings. “A lot of people ask to shadow me in clinic, and want to learn more about CHIP,” said Dr. Lin. “I encourage people to pursue their passion, and to be persistent in seeking out good mentors. Ask to meet with a lot of people, and try working with different people until you find a good match. You’ll intrinsically know when you find a good mentor, because it will feel right.”
She looks forward to learning more about CHIP, as well as links between cancer and cardiovascular disease. “We know that these two disease processes have shared risk factors, including aging, inflammatory diseases, smoking, high cholesterol and obesity,” said Dr. Lin. “Ultimately, we want to learn more about how people can age well and in good health. Inflammation and aging is a huge field of study, and CHIP dips into that as well. We are living longer, and we want those years to be quality years.”
When she’s not caring for patients or delving into the mysteries of CHIP, Dr. Lin enjoys crocheting, knitting, painting, drawing and reading.
- Elizabeth Chur