An exploratory study of environmental and nutritional determinants of early-stage clonal hematopoiesis in the elderly.

Clonal hematopoiesis of indeterminate potential (CHIP), defined by somatic mutations in hematopoietic cells without overt malignancy, is linked to increased risks of hematologic malignancies, cardiovascular disease, and mortality. However, the contribution of environmental exposures and lifestyle factors remains poorly understood. Our exploratory study characterized early-stage CHIP using a variant allele frequency cut-off > 0.1% in 888 well-phenotyped 70-year-olds leveraging ultra-deep targeted sequencing (mean coverage 8331X). Associations with dietary patterns, specific nutrient intakes, persistent organic pollutants (POPs), per- and polyfluoroalkyl substances (PFAS), heavy metals, and germline variants were evaluated. The prevalence of early-stage CHIP was 41.0%. Elevated blood cadmium levels were associated with an increased prevalence of non-DTA-CHIP (mutations occurring outside of DNMT3A, TET2, and ASXL1, odds ratio (OR) 2.13, 95% confidence interval (CI) 1.32-3.45), especially TP53-CHIP (OR 3.34, 95% CI 1.65-6.72). PCB-189 levels were positively linked to DNMT3A-CHIP (OR 1.42, 95% CI 1.13-1.79). Healthy dietary patterns were associated with decreased odds of TET2-CHIP (OR 0.88, 95% CI 0.78-0.98) whereas increased odds for TET2-CHIP were observed for higher intakes of vitamin B2 (OR 2.07, 95% CI 1.17-3.69). Higher intakes of vitamins B2 and B6 as well as smoking were associated with an increased prevalence of non-DTA CHIP (OR 2.35, 95% CI 1.03-5.33, OR 2.05, 95% CI 1.03-4.05, and OR 3.17, 95% CI 1.43-6.64, respectively). Our exploratory study suggests that the exposome may influence clonal selection in the bone marrow, but future studies are required to validate these factors and determine their clinical significance.