Clonal haematopoiesis of indeterminate potential and the role of inflammation in its association with atherosclerosis

Chronic inflammation drives atherosclerosis, and although it is heightened by ageing – the strongest predictor of cardiovascular disease (CVD), what instigates cardiovascular inflammation in ageing remains unclear. Clonal haematopoiesis of indeterminate potential (CHIP) is a common age-associated condition in which haematopoietic stem cells acquire somatic mutations, leading to clonal expansion and aberrant cellular functions. CHIP has been suggested to drive CVD via increased IL-1β from mutant clonal macrophages, but how this can be true for mutations in multiple unrelated genes is unclear. CHIP-driver mutations affect a wide range of genes with sometimes opposing biological functions and are therefore unlikely to universally converge on the same pathways to augment IL-1β production. Moreover, reports on IL-1β production with CHIP mutations are discordant. The work presented in this thesis demonstrates that disparate CHIP-driver mutations have overlapping but discordant effects on cytokine production in mouse macrophages. Notably, Nlrp3 inflammasome activity and IL-1β release are increased by Tet2 loss, and reduced by Dnmt3a mutation, despite both perturbations upregulating transcript for IL-1β. Conversely, Jak2 mutations have no effect on macrophage cytokine production or release. Therefore, immunomodulatory therapies under investigation for the cardiovascular sequelae of CHIP may need to be tailored to the specific driver mutation. CHIP is widely reported to associate with CVD, with the presumption that CHIP promotes atherogenesis, but the reverse could be true, particularly as cardiovascular inflammation promotes bone marrow turnover. Moreover, murine studies inferring causality have often used models of CHIP with supra-pathophysiologic levels of mutant bone marrow cells. We find that the hyperlipidaemic atherogenic environment and systemic inflammation do not drive expansion of heterozygotic Tet2, Dnmt3a and Jak2 mutant cells in experimental models. This in combination with null results in Mendelian randomisation analysis suggests that reverse causation does not underly the relationship between CVD and CHIP. We also find that CHIP does not universally drive augmented atherogenesis in experimental models, uncovering gene-specific sexual dimorphism, with atherogenesis driven by Tet2 mutant cells in females only, Jak2 mutants in males only, and no effect of Dnmt3a mutant cells in either sex. Thus, cardiovascular risk stratification in CHIP needs to consider the mutation and the sex of the individual. Lastly, no treatments exist to prevent or treat CHIP or it’s wide-ranging haematological and non-haematological sequalae. We use Mendelian randomisation to demonstrate that statins, ezetimibe, calcium channel blockers and vitamin C may all represent promising therapeutic options to explore for CHIP prevention. In conclusion, the work presented in this thesis furthers our understanding of the bidirectional relationship between CHIP and CVD, and the role of inflammation in this. We demonstrate CHIP-driven atherogenesis and inflammation to be nuanced and dependent on sex and mutation-type. Thus, CHIP with different mutational drivers should be treated as separate entities with disparate pathophysiology and sequelae.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Carter, Paul

Advisor dc:contributor.advisor

• Clarke, Murray

• Atherosclerosis
• Cardiovascular disease
• Clonal haematopoiesis
• Inflammation

Licence

• https://www.repository.cam.ac.uk/bitstreams/b8a04bde-6a28-4bee-a51f-c020fbd22b3c/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

Author Identifier

0000-0002-9146-7540

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/382610