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EPIDEMIOLOGY

Infection risk associated with clonal hematopoiesis of indeterminate potential is partly mediated by hematologic cancer transformation in the UK Biobank

Leukemia volume 37, pages 2306–2308 (2023)Cite this article

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Clonal hematopoiesis of indeterminate potential (CHIP) is a recently described condition wherein a sizeable proportion of an individual’s circulating blood cells are derived from a single mutated hematopoietic stem cell [1]. The development of CHIP is a common consequence of aging: more than 10% of individuals over age 65 are affected. While CHIP is a precursor state for myeloid lineage hematologic cancers, malignant transformation is a rare event: only 0.03–1% of CHIP cases transform to cancer per year [2]. Importantly, CHIP has been associated with an increased risk of premature death and a greater burden of chronic disease across organ systems [3,4,5,6,7,8]. A central mechanism for this pan-chronic disease risk is the upregulation of pro-inflammatory signaling by CHIP-affected white blood cells, particularly monocytes and macrophages [3, 7,8,9,10]. There is a comparative paucity of published studies on the role of CHIP in infection risk and on the potential effects of CHIP on the function of white blood cells important in infection such as neutrophils; the literature to date is mostly limited to epidemiologic studies assessing the role of CHIP in COVID-19 and HIV infections [11,12,13]. A related but distinct clonal blood state, clonal mosaic chromosomal alterations, has been associated with an increased risk for diverse types of infection [14].

In this work, we assess the association between CHIP and infection risk. We use data from a large observational cohort study, the UK Biobank (UKB), to determine the association between CHIP status at enrollment with incident sepsis, bacterial, and viral infections over a 12-year period. The UKB is a large observational cohort comprised of over 500,000 individuals residing in the United Kingdom who were enrolled between 2006 and 2010. Demographic data, including age, sex, and health habits, were collected at baseline, and clinical outcome data are collected on an ongoing basis from electronic health records (hospital and general practitioner records), cancer registries, and death registries. A median of 12.4 years [interquartile range, 11.6–13.1] of clinical follow-up data are available per participant. We previously determined the CHIP status for all participants with available whole exome data in the UKB (N = 453,510); the details of this method are described elsewhere [2]. Individuals with a history of hematologic cancer at enrollment are excluded from the CHIP dataset, and incident hematologic cancer diagnoses were defined using records from the UKB cancer registry. We defined sepsis, bacterial infection, and viral infection cases by searching the UKB summary diagnoses data columns for International Classification (ICD)-10 codes corresponding to the definitions outlined by Trinder et al. [15]. Hospitalizations related to COVID-19 (ICD-10 code U07) were added to the viral infection case definition. Incident infection cases were defined as the first infection noted after enrollment. Outcome events were censored at participant death, known loss-to-follow-up, administrative censor date (July 2021), and where indicated, 6 months prior to the date of diagnosis of myeloid malignancy.

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Fig. 1: Association between CHIP and incident infections is partly mediated by transformation to hematologic cancers.

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Authors and Affiliations

  1. Department of Medicine, Queen’s University, Kingston, ON, Canada

    Caitlyn Vlasschaert

  2. Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA

    Elvis Akwo & Cassianne Robinson-Cohen

  3. Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada

    Elina K. Cook & Michael J. Rauh

  4. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Matthew B. Lanktree

  5. Population Health Research Institute (PHRI), Hamilton, ON, Canada

    Matthew B. Lanktree

  6. Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada

    Matthew B. Lanktree

  7. Department of Medicine, Division of Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Alexander G. Bick

Authors
  1. Caitlyn Vlasschaert
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Contributions

CV, EA, and AJB designed the study. CV conducted the analyses and wrote the manuscript. EA, EKC, CR-C, MBL, MJR, and AJB provided critical feedback on the results and manuscript draft.

Corresponding author

Correspondence to Alexander G. Bick.

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Competing interests

AGB is a co-founder, equity holder, and on the scientific advisory board of TenSixteen Bio. MBL has received speaking and advisory board fees from Bayer, Otsuka, Reata and Sanofi. All other authors declare no conflicts of interest.

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Vlasschaert, C., Akwo, E., Robinson-Cohen, C. et al. Infection risk associated with clonal hematopoiesis of indeterminate potential is partly mediated by hematologic cancer transformation in the UK Biobank. Leukemia 37, 2306–2308 (2023). https://doi.org/10.1038/s41375-023-02023-7

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