Clonal haematopoiesis of indeterminate potential (CHIP) is the acquisition of somatic mutations in leukaemia-associated genes in haematopoietic progenitors with age. It increases the risk of haematological malignancy (HM), cardiovascular disease (CVD) and mortality mediated by CHIP-associated inflammation, with larger clones posing higher risks. Statins have been found to reduce the risk of progression from myelodysplastic syndrome to acute myeloid leukaemia and have also shown efficacy in vitro against TET2 deficient AML cell lines. However, their effect on CHIP has not been described. This study characterises the English Longitudinal Study of Ageing as a novel longitudinal CHIP cohort, through genetic analysis of 13270 longitudinal peripheral blood samples from participants aged over 50. Using logistic and robust regression analysis, we show that statin therapy is associated with reduced TET2 CHIP clonal expansion in a gene specific manner. We also find that statin primary prevention is associated with significantly lower incidence of myocardial infarction and stroke in individuals with CHIP compared to controls. These findings provide evidence that a commonly prescribed mediation with a well characterised safety profile may modify the natural history of TET2 CHIP, thereby mitigating its associated health risks.

JH is employed by Asgard Therapeutics.

The English Longitudinal Study of Ageing is funded by the National Institute on Aging (grant number RO1AG17644) and the National Institute for Health and Care Research (198/1074-02). EP is funded by the Cancer Research UK Advanced Clinician Scientist award A24873. ENM is funded by the Medical Research Council (grant reference MR/X001423/1). The authors thank the ELSA project team members, the National Centre for Social Research and ELSA participants for their time and commitment to the study. SD is supported by the BHF Data Science Centre / CVD-COVID-UK/COVID-IMPACT consortium, led by HDR UK (SP/19/3/34678), NIHR Biomedical Research Centre at University College London Hospital NHS Trust (UCLH BRC), BHF Accelerator Award (AA/18/6/24223), Multimorbidity Mechanism and Therapeutic Research Collaborative (MMTRC, grant number MR/V033867/1), NIHR-UKRI CONVALESCENCE study, and the Longitudinal Health and Wellbeing COVID-19 National Core Study, which was established by the UK Chief Scientific Officer in October, 2020, and funded by UKRI (grant references MC_PC_20030 and MC_PC_20059).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Research Ethics Committee of South Central - Berkshire (NHS Health Research Authority) gave ethical approval for this work.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The ELSA data is available on UK Data Service. All original code has been deposited at https://github.com/e-nuttallmusson/ELSA_statins_clonal_dynamics and is publicly available as of the date of publication. Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon reasonable request, subject to General Data Protection Regulations.