Clonal Hematopoiesis of Indeterminate Potential (CHIP) Center

What is CHIP?

In the bone marrow, cells called hematopoietic stem cells are constantly making new blood cells to keep us healthy. As we age, the DNA in our stem cells can accumulate changes or mutations over time. These mutations can occur in certain genes that can lead to alterations in cell survival and proliferation. When these mutations cause one group of blood cells to grow more than others, this is called “clonal hematopoiesis”. This term describes the process when a specific group of blood cells with mutations gains an advantage, leading to increased proliferation and survival.

However, most of these DNA mutations do not affect the blood cells or lead to noticeable symptoms or disease. This is why the condition is referred to as CHIP—Clonal Hematopoiesis of Indeterminate Potential. The term “indeterminate potential” reflects the uncertainty of what these mutations mean for your health. Research has since shown that people with CHIP are at an increased risk of certain health problems, such as heart disease, inflammatory diseases, and blood cancers.

what is chip

How does CHIP affect heart disease?

CHIP is common as you age, occurring in about 20% of healthy adults over 70 years of age. This can increase in patients who have cancer and received chemotherapy and radiation. Individuals with CHIP are at increased risk of developing heart disease and blood cancers. There is almost a 2-4 times increased risk of cardiovascular disease (CVD) and stroke compared to individuals without CHIP, making the presence of CHIP as potent a cardiac risk factor as smoking, hypertension or elevated cholesterol. The risk of developing blood cancers is less, with an increase of 2% per year compared to individuals without CHIP.

Additional studies have broadened the role of CHIP in CVD, showing that individuals with CHIP have accelerated disease and worse outcomes in heart failure (HF), aortic stenosis, peripheral artery disease (PAD), thrombosis/blood clots, atrial fibrillation (AF) and potentially pulmonary hypertension.

CHIP most commonly arises due to mutations in the epigenetic regulators DNMT3A and TET2. Pre-clinical model data show that immune cells with these mutations can cause activation of the NLRP3 inflammasome complex, an innate immune system of proteins that stimulates inflammation, which functions upstream of signaling protein cytokines IL-1b and IL-6. Activation of these cytokines involves chemical signaling and communication between white blood cells and other organ tissues, which can lead to inflammation. Another commonly mutated CHIP gene is JAK2. Mutations in the JAK2 gene can also lead to inflammasome activation and formation of blood clots.

CHIP CVD

CHIP-CVD clinic and the UCSF CHARIOT Study

Given that CHIP becomes more common as we age and is a significant risk factor for CVD, it is crucial individuals are aware about CHIP. Diagnosing CHIP involves a special blood test that can identify specific genetic mutations in the blood cells. This test is currently not part of routine care for healthy individuals. 

Due to the lack of both CHIP sequencing in cardiology care and a registry of individuals with CHIP, UCSF has established the CHIP, cARdiovascular dIsease and OuTcomes (CHARIOT) Registry and Biobank. This initiative encompasses the recruitment of individuals with CHIP, CHIP sequencing techniques, ongoing follow-up, and approaches for CHIP screening and monitoring. The CHARIOT registry was created to enhance our understanding of cardiovascular disease and outcomes for individuals with CHIP, serving as a foundation for integrating CHIP into healthcare practices.

CHIP-CVD clinic

The establishment of the CHIP-CVD clinic at UCSF will provide tailored screening and cardiovascular care for patients with mutations in CHIP-related genes. Through this clinic and the CHARIOT study, we will build a registry of patients with CHIP to better understand the clinical outcomes and comorbidities associated with CHIP. Through collaborations with the CHIP-CVD clinic, biobank, hematology/oncology and pathology divisions, this data will allow us to better understand how CHIP develops in patients, identify “at risk” populations for CVD, and identify genes and pathways involved in the pathogenesis of CHIP.

Who should be referred to the CHIP-CVD clinic:

  • Patients who are part of the CHARIOT study and through sequencing are found to have CHIP, will be referred to the CHIP-CVD clinic.
  • Patients who are interested in knowing if they have CHIP and wish to undergo sequencing using our research-based test can be referred to the CHIP-CVD Clinic.
  • Patients who have undergone next-generation sequencing for other reasons and are found to have CHIP or mutations in CHIP-related genes, including solid tumor sequencing, surveillance sequencing as part of cancer survivorship care, or patients who are being evaluated for stem cell donation.
  • Patients with precursor blood disorders or blood cancers and found to have mutations in CHIP-related genes, including cytopenia, monoclonal gammopathy of unknown significance (MGUS), multiple myeloma (MM), smoldering multilpe myeloma (SMM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), chornic myeloid leukemia (CML), polycythemia vera (PCV), essential thrombocytosis (ET), or primary myelofibrosis (PMF).

What to expect from the CHIP-CVD clinic:

Patients in the CHIP-CVD clinic will receive a comprehensive cardiovascular evaluation to develop a personalized, detailed and tailored plan for CVD risk reduction and/or treatment of their CVD disease.  Specific biomarkers will also be collected for the CHARIOT study, including diabetes marker HbA1c, fasting lipids, thyroid tests, troponin, BNP, NT-proBNP, inflammatory markers such as C-reactive protein (CRP), high-sensitivity CRP, erythrocyte sedimentation rate (ESR) and a coronary calcium score (CAC). Serial CHIP sequencing will be performed every 3-5 years. Patients will also complete a survey on CHIP, which will help build a better CHIP-CVD clinic.

Patients who are not followed by hematology and oncology will be referred to the Precursor Hematology Clinic as part of a multi-disciplinary care team.  There, additional tests may be performed, including bone marrow biopsy and next-generation sequencing using a certified and regulated clinical test for CHIP.

chip clinic

In the future, patients in the CHIP-CVD clinic will have access to up-to-date new treatments for CHIP or enrollment in clinical trials for new CHIP specific therapies.

 

References

  1. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019 Nov 1;366(6465):eaan4673. doi: 10.1126/science.aan4673. PMID: 31672865; PMCID: PMC8050831.
  2. Libby P, Jaiswal S, Lin AE, Ebert BL. CHIPping away at the pathogenesis of heart failure. JAMA Cardiology [Internet]. 2019 Jan 1;4(1):5. Available from: https://doi.org/10.1001/jamacardio.2018.4039
  3. Libby P, Sidlow R, Lin AE, Gupta D, Jones LW, Moslehi J, Zeiher A, Jaiswal S, Schulz C, Blankstein R, Bolton KL, Steensma D, Levine RL, Ebert BL. Clonal Hematopoiesis: Crossroads of Aging, Cardiovascular Disease, and Cancer: JACC Review Topic of the Week. J Am Coll Cardiol. 2019 Jul 30;74(4):567-577. doi: 10.1016/j.jacc.2019.06.007. PMID: 31345432; PMCID: PMC6681657.
  4. Lin AE, Bapat AC, Xiao L, Niroula A, Ye J, Wong WJ, Agrawal M, Farady CJ, Boettcher A, Hergott CB, McConkey M, Flores-Bringas P, Shkolnik V, Bick AG, Milan D, Natarajan P, Libby P, Ellinor PT, Ebert BL. Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation. Circulation. 2024 Apr 30;149(18):1419-1434. doi: 10.1161/CIRCULATIONAHA.123.065597. Epub 2024 Feb 15. PMID: 38357791; PMCID: PMC11058018.
  5. Svensson EC, Madar A, Campbell CD, He Y, Sultan M, Healey ML, Xu H, D'Aco K, Fernandez A, Wache-Mainier C, Libby P, Ridker PM, Beste MT, Basson CT. TET2-Driven Clonal Hematopoiesis and Response to Canakinumab: An Exploratory Analysis of the CANTOS Randomized Clinical Trial. JAMA Cardiol. 2022 May 1;7(5):521-528. doi: 10.1001/jamacardio.2022.0386. PMID: 35385050; PMCID: PMC8988022.
  6. Sidlow R, Lin AE, Gupta D, Bolton KL, Steensma PD, Levine RL, Ebert BL, Libby P. The Clinical Challenge of Clonal Hematopoiesis, a Newly Recognized Cardiovascular Risk Factor. JAMA Cardiology. 2020, May 27, 2020;5(8):958–961 PMID: 32459358. doi: 10.1001/jamacardio.2020.1271.