The genetic, clinical and immune landscape of clonal hematopoiesis across adulthood in the multi-ancestry Mount Sinai Million cohort

Esai Selvan, M., Ashraf, N., Pradeep, R., Giordano, L., Dougherty, M., Chevelev, P., Neuse, C. J., Nathan, D. I., Marcellino, B. K., Klein, R. J., et al.

10.64898/2026.10.22.26366221 · was preprinted

biomedical

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Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), the age-associated expansion of blood cell clones carrying acquired driver mutations, remains less well characterized in young adults, across genetic ancestries, and in clinical populations. We analyzed whole-exome sequencing and longitudinal electronic health record (EHR) data from 59,598 adults in the Mount Sinai Million Health Discoveries Program, an urban, multi-ancestry hospital-based cohort that includes substantial representation of African ([~]35%) and Admixed American genetic ancestry ([~]15%) and young adults aged 18-39 years ([~]30%). After sample QC, separate analyses were performed in discovery (n = 28,051) and validation (n = 26,938) cohorts defined by sequencing platform and combined by meta-analysis. CHIP was detected in 8.5% of participants in each cohort and in 4.0% of young adults, with DNMT3A, TET2, ASXL1, and PPM1D the most frequently mutated genes. Prevalence and clone size increased with age across ancestry groups. After adjusting for age, participants of African ancestry had lower CHIP prevalence than those of European ancestry in both cohorts (discovery: OR=0.86, 95% CI = 0.78-0.95, p=0.002; validation: OR=0.84, 95% CI = 0.75-0.93, p=0.001). Participants of Admixed American ancestry showed a similar trend. Higher systemic immune-inflammation index (SII) was associated with CHIP after adjusting for age, sex and ancestry in both cohorts (pooled OR=1.30, 95% CI = 1.15-1.48, p=4.78e-5). Heterozygosity at an HLA class II locus HLA-DPA1 was associated with 7% lower odds of overall CHIP (pooled OR=0.93, 95% CI = 0.87-0.99, p=0.03). Driver-stratified analyses revealed distinct HLA class II nominal association patterns for DNMT3A- and TET2-mutant CHIP. Particularly, HLA-DQB1 heterozygosity associated with lower odds of TET2-mutant CHIP (pooled OR=0.84, 95% CI = 0.70-1.00, p=0.05), HLA-DQA1 and HLA-DOB heterozygosity associated with higher odds of DNMT3A-mutant CHIP (pooled OR=1.19, 95% CI = 1.00-1.42, p=0.05; pooled OR=1.12, 95% CI = 1.01-1.25, p=0.03 respectively). Longitudinal EHR analyses revealed CHIP associations with several incident diseases that varied by driver gene and clone size. The broadest pattern of associations involved high-risk CHIP genes and encompassed hematologic malignancies, solid tumors, cardiovascular outcomes, hypertension, and COPD. High-VAF clones were the main drivers of these associations. Among adults aged [≥] 40 years, phenome-wide analyses identified a Bonferroni-significant association with incident myeloproliferative disease and nominal associations with incident pancytopenia, anemia, cardiomegaly, and chronic renal failure. Young-adult CHIP was nominally associated with incident nodular goiter and esophageal disease. These findings characterize CHIP across adulthood and genetic ancestry and reveal inherited immune variation and systemic inflammation as correlates in a hospital-based population.

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