CHIP – Connecting Ageing and Disease 

What is CHIP?

CHIP, short for Clonal hematopoiesis of indeterminate potential, is a condition characterised by the presence of a genetically distinct sub-population of blood cells (1). Therefore, the blood cells comprising the subpopulation all present with a unique genetic mutation. This happens because of mutations in hematopoietic (i.e. blood) stem cells (HSCs), which are proposed to give a competitive advantage to these cells to proliferate (1).

Think of random mutations in animals – although they can have no effect on the animal, and indeed can often have a negative effect, sometimes they can lead to an advantageous characteristic that leads to an allele increasing in prevalence in a population. Similarly, these mutations in HSCs cause for the VAF (Variant Allele Frequency, i.e. the relative proportion of cells having a particular allele) of a particular mutation to rise in a person’s blood. However, unlike with evolution, these mutations are somatic, meaning that they cannot be passed downto offspring. The prevalence of CHIP depends on the VAF employed in detecting subpopulations within a patient’s blood cells. With a minimum VAF of 2%, CHIP has been shown to be prevalent amongst around 12% of 70–89-year-olds and around 20% of those over 90 (5), whereas when the minimum VAF is 0.01%, the incidence of CHIP and its associated mutations increase (4). However, due to the significance of a VAF under 2% being unknown and likely minor, the current definition of CHIP requires forthere to be a VAF of over 2%. It has been asserted that CHIP has a direct correlation with age; prevalence amongst those under 40 years of age is almost 0 (5). Thus, researchers conjecture that understanding CHIP may be a way of understanding why age is currently the “single best” predictor for all-cause mortality– age does not provide mechanistic explanations, but perhaps CHIP will.

Why is it important?

CHIP, by itself is not necessarily a dangerous condition. However, statistical analysis has shown numerous associations between CHIP and a multitude of diseases and conditions. One striking association is with hematological cancers, where there is a tenfold risk of haematological (i.e. blood) cancers in individuals with CHIP (6). One particular explanation for this is that in most cancers in the blood, there are multiple “driver mutations” – which are mutations which provide a “selective growth advantage” to cells, thus leading to cancer/tumour development (7) – whereas in CHIP, over 90% of cases only exhibit one mutation. It is hypothesized that CHIP is a sort of “premalignant” state – an intermediary between a typical and normal genome and malignancy (i.e. cancer). Furthermore, CHIP has associations with many cardiovascular diseases. It is hypothesized that the same mutations causing for disproportionate clonal expansion (i.e. subpopulations forming) cause for increased inflammation in the body. Perhaps this increased inflammation leads to mechanisms such as increased monocyte recruitment to tissues, including the arterial intima where they differentiate into macrophages, contributing to the formation and growth of atheromas (i.e. plaques that build up in arteries). More on this can be found in the third referenced article. These associations, amongst others, mean that clinicians can potentially target CHIP to reduce risk of developing diseases as a whole in patients. What is the future of CHIP research? It is all well and good for this condition to be identified in humans, but how does the identification of CHIP in patients translate to actionable treatments for clinicians? One promising treatment is using inflammatory blockade, i.e. reducing inflammation in the blood.

One such drug is Canakinumab, which is an “interleukin antagonist”, which works by blocking chemicals (interleukins are inflammatorycytokines) that cause inflammation in the body. Canakinumab is still in clinical trials for usage with CHIP, and does not seem to be the definitive answer to the problems caused by CHIP – blocking inflammatory cytokines may cause as many problems as it solves, potentially compromising the immune system of patients by preventing effective immune response in the body in response to pathogens, trauma or cancer. Furthermore, as no drugs are currently available for treatment of patients with CHIP, it is generally accepted that patients shouldn’t be screened for CHIP. Thus, we see that there are many questions left to be answered, with comprehensive mechanistic explanations for many associations still lacking. Furthermore, clinicians currently lack any way of preventing CHIP, and by virtue of a lack of understanding of why CHIP is a risk factor, clinicians cannot do anything substantial to prevent development of diseases in patients with the condition. More research is currently needed to connect the dots between CHIP and the diseases it is linked to.

Keywords:

Cytokines: Proteins in the body that act as messengers between immune system cells (8)

Allele: One of two or more versions of a gene. Different alleles produce variations in inherited characteristics, such as eye colour (8)

Stem Cells: an undifferentiated cell of a multicellular organism which is capable of giving rise to indefinitely more cells of the same type, and from which certain other kinds of cell arise by differentiation (8)

Somatic Mutations: A somatic mutation describes any alteration atthe cellular level in somatic tissues occurring after fertilization. These mutations do not involve the germline and consequently do not pass on to offspring (9)

Monocytes: White blood cells that protect the body from disease by attacking and consuming foreign particles (8)

Macrophage: A type of white blood cell that destroys cell debris, bacteria, and foreign agents (8)

Atheroma: An abnormal build-up of fatty plaque inside an artery (8)

Synoptic Links: GCSE: 4.3.1.6: Human defence systems (the immune system and its constituent cells) 4.6.2.1 Variation (how and why mutations arise in cells)

A-Level: 3.2.4 Cell recognition and the immune system ( the immune system and its constituent cells) 3.4.3 Genetic diversity can arise as a result of mutation or during meiosis (genetic mutations) 3.8.1 Alteration of the sequence of bases in DNA can alter the structure of proteins (How mutations can effect cells) 3.8.2.3 Gene expression and cancer (Cancer and cell genomes)

References

1. Jan M, Ebert BL, Jaiswal S. Clonal hematopoiesis. Seminars in Hematology [Internet]. Elsevier BV; 2017;54(1):43–50. Available from:http://dx.doi.org/10.1053/j.seminhematol.2016.10.002.
2. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-RelatedClonal Hematopoiesis Associated with Adverse Outcomes. New England Journal of Medicine [Internet]. Massachusetts Medical Society; 2014; 371(26):2488–98. Available from: http://dx.doi.org/10.1056/nejmoa1408617.
3. Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nature Reviews Cardiology [Internet]. Springer Science and Business Media LLC; 2019;17(3):137–44. Available from:http://dx.doi.org/10.1038/s41569-019-0247-5.
4. Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature [Internet]. Springer Science and Business Media LLC; 2018; 559(7714):400–4. Available from: http://dx.doi.org/10.1038/s41586-018-0317-6.
5. Bowman RL, Busque L, Levine RL. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell [Internet]. Elsevier BV; 2018; 22(2):157–70. Available from: http://dx.doi.org/10.1016/j.stem.2018.01.011.
6. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-RelatedClonal Hematopoiesis Associated with Adverse Outcomes. New England Journal of Medicine. 2014 Dec 25;371(26):2488–98.
7. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature [Internet]. 2009 Apr;458(7239):719–24. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821689/
8. Harvard Health Publishing. Medical Dictionary of Health Terms: Harvard Health [Internet]. Harvard Health. Harvard Health; 2011 [cited 2024 Jan 28]. Available from: https://www.health.harvard.edu/a-through-c
9. Miles B, Tadi P. Genetics, Somatic Mutation [Internet]. StatPearls Publishing; 2024 [cited 2024 Jan 28]. Available from:https://pubmed.ncbi.nlm.nih.gov/32491819