Clonal hematopoiesis may precede the diagnosis of aplastic anemia by several years Open Access

• We performed a community-based cohort study to investigate the association between CH and AA.

• CH may occur prior to the clinical diagnosis of AA by several years, particularly in those with SRSF2, TET2, ASXL1, and DNMT3A mutations.

Aplastic anemia (AA) is a bone marrow failure syndrome resulting from the immune destruction of hematopoietic stem cells. Clonal hematopoiesis (CH) is characterized by expansion of progenitor hematopoietic stem cells that harbor leukemogenic driver mutations. It has previously been shown that individuals with AA have a high prevalence of CH. However, the association between CH and AA remains unknown. We conducted a prospective, matched cohort study within the UK Biobank during 2006-2022. Individuals with CH were ascertained based on whole exome sequencing data. For each individual with CH, we randomly selected ten CH-free individuals, matched by sex, birth year, and ethnicity from the study population. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) of AA associated with CH by Cox regression model. We also studied the association by different mutations of CH. We identified 14,471 individuals with CH, and 144,323 matched individuals free of CH. Individuals with CH had a higher risk of AA (HR 2.72, 95% CI: 2.16-3.43), compared to reference group. The risk increase was greater for individuals with CH mutations in SRSF2 (HR 19.35, 95% CI: 11.07-33.80), TET2 (HR 4.45, 95% CI: 3.14-6.29), ASXL1 (HR 2.06, 95% CI: 1.06-4.00), or DNMT3A (HR 1.88, 95% CI: 1.31-2.70). In conclusion, CH may precede the diagnosis of AA, particularly in those with SRSF2, TET2, ASXL1, and DNMT3A mutations. Further studies are needed to understand the nature of this association and potential shared pathogenic mechanisms between CH and AA.