Age-related blood cell mutations affect heart disease risk in different ways, study finds

Cambridge researchers have revealed that different genetic changes in blood cells affect heart disease risk in sex-specific ways, highlighting the need for more targeted approaches to improve cardiovascular health.

A study published in JCI Insight and led by Paul Carter, Lauren Kitt and Murray Clarke at the Department of Medicine, University of Cambridge, shows how Clonal Haematopoiesis of Indeterminate Potential (CHIP) mutations alter the inflammatory response differently and drive atherosclerosis – a chronic disease ultimately leading to heart attack and stroke, the number one cause of death globally – in a sex-dependent manner.

CHIP occurs when blood stem cells acquire somatic mutations, leading to clonal expansion in the bone marrow and mutant circulating blood cells produced from them. CHIP is common in older people and confers a markedly increased risk of cardiovascular disease, proposed to be due to increased inflammation from mutant macrophages infiltrating into atherosclerotic plaques. 

But, how CHIP mutations in genes with discordant functions converge on the same mechanism is puzzling. Reports of the effects of mutations on clonal expansion, atherosclerosis and inflammation are conflicting, and many studies focus on biallelic mutations that typically don’t occur in humans.

The team from the Clarke Lab at the VPD-HLRI investigated the effect of three key CHIP mutations on macrophage cytokines, clonal expansion and atherosclerosis in parallel. Their work reveals that while Tet2 mutations increase cytokines & inflammasome activation, Dnmt3aRH mutations decrease them, and Jak2VF has no effect. In contrast to recent reports, only Tet2 mutant cells expand in murine CHIP models, with both Dnmt3aRH and Jak2VF mutant cells lost. Importantly, clonal expansion of mono-allelic mutants is unaffected by systemic inflammation or hyperlipidemia, while human Mendelian randomisation shows CHIP to drive atherosclerosis, and not the reverse. Most significantly, CHIP models increase atherosclerosis in female Tet2 and male Jak2VF only, and not Dnmt3aRH mutants. 

Results from the study questions the findings of several key papers in the field but aligns with multiple observational studies in humans, suggesting that CHIP should not be treated as a single condition. Understanding these differences could help researchers and clinicians better predict an individual’s risk of heart disease and design more targeted treatments in the future.

Our work emphasises that CHIP consists of biologically distinct subtypes with different inflammatory profiles and cardiovascular consequences. CHIP mutations should be studied as separate heterogenous entities to better define individual risk and guide therapy. We also identify previously unrecognised sex differences in the association between CHIP and atherosclerosis. These differences may contribute to the late-life rise in atherosclerotic disease in women and warrant further investigation as a potential target to improve women’s cardiovascular health.

Paul Carter, NIHR Clinical Lecturer in Cardiology at the Department of Medicine, University of Cambridge, and first author of the study

This work is funded by the British Heart Foundation, supported by the BHF Cambridge Centre for Research Excellence and the Cambridge NIHR Biomedical Research Centre.