Clonal Hematopoiesis of Indeterminate Potential, or CHIP, is an age-related condition involving the accumulation of acquired genetic changes in blood cells. This phenomenon is defined by the presence of a clone—a population of blood cells derived from a single mutated blood stem cell. While often remaining a silent condition, it can be incidentally detected through advanced genetic testing, revealing a subtle shift in the blood’s composition. The presence of these mutated cells, even without signs of disease, has opened a new area of research into how the aging process impacts health.
Defining Clonal Hematopoiesis
CHIP arises from somatic mutations, which are genetic changes acquired during a person’s lifetime rather than inherited. These mutations occur spontaneously in hematopoietic stem cells, the precursor cells in the bone marrow responsible for producing all mature blood cells. Certain mutations grant the stem cell a competitive edge over healthy counterparts.
This competitive advantage leads to clonal expansion, allowing the mutated stem cell to divide and multiply more successfully. This single mutated cell generates a large population, or clone, of mature blood cells carrying the same mutation. CHIP is officially classified when the mutated clone comprises at least 2% of the blood cells and the individual shows no other signs of a blood disorder or malignancy.
The term “indeterminate potential” highlights that clonal expansion is not a disease itself but a risk factor for future health problems. This phenomenon is strongly associated with aging, found in less than 1% of the population under age 40, but in 10% to 20% of individuals over 70.
Genes Involved and How CHIP Develops
The mutations driving CHIP are typically found in genes involved in the development of blood cancers. The three most common driver mutations are in the genes DNMT3A, TET2, and ASXL1, accounting for about 80% of all CHIP cases. These genes regulate the complex process of epigenetic modification, controlling when and how other genes are expressed.
DNMT3A and TET2 are involved in DNA methylation, a mechanism that alters gene expression without changing the underlying DNA sequence. Loss of function in these genes perturbs the normal differentiation and self-renewal of blood stem cells, granting the mutated cell a selective growth advantage. The ASXL1 gene mutation is also an epigenetic regulator that contributes to clonal fitness.
CHIP is often identified incidentally when advanced next-generation sequencing (NGS) technology is used for other purposes. The mutations are not the cause of an immediate disease, but the presence of the clone indicates a pre-existing genetic vulnerability within the blood system. The size of the clone, measured by the Variant Allele Frequency (VAF), influences the level of associated health risk.
CHIP’s Link to Disease Risk
The significance of CHIP lies in its association with a heightened risk for two distinct categories of health problems: hematological malignancy and cardiovascular disease. While the annual risk of progression to a blood cancer is relatively low, ranging from 0.5% to 1.0%, this is still a significantly elevated risk compared to the general population. CHIP is considered a pre-leukemic state, preceding the development of myeloid malignancies like Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML).
The second major health risk is a two-fold increase in the risk of atherosclerotic cardiovascular disease, independent of traditional risk factors. This link is driven by the inflammatory nature of the mutated blood cells, particularly those carrying TET2 and DNMT3A mutations. These mutated hematopoietic stem cells produce macrophages and other immune cells that are predisposed to chronic activation.
This state of chronic, low-grade inflammation promotes the progression of atherosclerosis, which is the buildup of plaque in the arteries. The mutant cells contribute to this process by increasing the expression of pro-inflammatory signals, such as IL-1β and IL-6. This accelerates plaque formation and instability in blood vessel walls, explaining why CHIP is associated with a higher incidence of heart attack, stroke, and heart failure.
Clinical Approach to Monitoring CHIP
The current clinical approach focuses primarily on surveillance and aggressive risk factor modification, as there is no standard curative treatment available to eliminate the clone. Monitoring involves routine check-ups, including a complete blood count (CBC) every three to six months, to track for signs of progression toward a blood disorder.
For managing the cardiovascular risk, which is often the more immediate concern, the recommendation is to aggressively manage all traditional risk factors. This involves strict control of blood pressure, cholesterol levels, and diabetes, often guided by preventive cardiology specialists. Patient education is a significant component of the clinical strategy, ensuring individuals understand the condition and the importance of healthy lifestyle behaviors to mitigate potential risks.
Ongoing research is exploring whether specific drug interventions, such as anti-inflammatory agents or low-dose chemotherapy, could stabilize or reduce the size of the clone and lower the associated disease risks. Management requires a multidisciplinary approach involving hematologists and cardiologists to provide individualized risk assessment and guidance. The Clonal Hematopoiesis Risk Score (CHRS) is being developed to help physicians better stratify patients into low- or high-risk groups for progression to malignancy.