Adverse Early-Life Factors Associated with Clonal Hematopoiesis of Indeterminate Potential in Later Life

Background: Clonal hematopoiesis of indeterminate potential (CHIP) can lead to adverse outcomes and may begin early in life. This study aimed to investigate the association between early-life events and CHIP. Methods: In total, 456,658 participants from U.K. Biobank without baseline hematologic malignancies were enrolled. Exposures included 17 early-life events, including reproductive, childhood adversity, and pre-adulthood development factors. CHIP was derived from whole-exome sequencing for mutations in 74 driver genes. Logistic regressions were used to estimate associations between early-life events and the presence of any CHIP or gene-specific CHIP mutations. Results: Overall, 17,513 (3.8%) individuals with any CHIP were identified, among which the most common subtype was DNMT3A (2.4%), followed by TET2 (0.6%) and ASXL1 (0.4%). Compared with participants without sexual abuse in childhood, those who experienced such abuse were positively associated with CHIP (OR 1.35, 95% CI 1.02-1.80), especially among ASXL1, JAK2, and TP53 mutations. Long-term/recurrent antibiotic use as a child or teenager was positively associated with CHIP (OR 1.11, 95% CI 1.02-1.21), especially among DNMT3A, ASXL1, and EP300 mutations. Sex-specific differences were observed, including sexual abuse associated with ASXL1-CHIP in males and JAK2/TP53-CHIP in females and long-term/recurrent antibiotic use associated with DNMT3A/EP300-CHIP in males and ASXL1-CHIP in females. Furthermore, we identified circulating proteomic biomarkers shared by six pairs of early-life factors and gene-specific CHIP mutations, including B2M for sexual abuse and JAK2-CHIP. Conclusions: Early-life factors, especially sexual abuse and long-term/recurrent antibiotic use, were positively associated with the presence of CHIP, particularly among specific gene mutations, offering potential targets for susceptibility and pathogenesis exploration.