Poster Presentation GENEMAPPERS 2026

Association between CHIP-status and epigenetic markers of aging with time (#82)

Robert L O'Reilly 1 , Philip Harraka 1 , Pierre-Antoine Dugue 1 2 3 , Jared Burke 1 , Pin-Yen Chen 1 , Paul Yeh 4 5 , Kerryn Howlett 1 4 , Kiarash Behrouzfar 4 , Amanda Rewse 1 , Helen Tsimiklis 1 , Grace Thomas 6 7 , Domenic Sacca 6 7 , Kristen J Bubb 7 8 , Stephen J Nicholls 6 7 , Roger L Milne 1 2 9 , Melissa C Southey 1 2 3
  1. Precision Medicine, School of Clinical Sciences at Monash Health, , Monash University, Melbourne, VIC
  2. Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC
  3. Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  4. Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC
  5. Monash Haematology, Monash Health, Melbourne, VIC
  6. Victorian Heart Hospital, Melbourne, VIC
  7. Victorian Heart Institute, Monash University, Melbourne, VIC
  8. Biomedicine Discovery Institute, Monash University, Melbourne, VIC
  9. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, , The University of Melbourne, Melbourne, VIC

Introduction

Clonal haematopoiesis of indeterminate potential (CHIP) is a common age-related acquisition of somatic mutations in haematopoietic stem cells leading to clonal expansion. The incidence of CHIP increases with age and has found to be associated with cardiovascular disease, chronic inflammatory disease, and haematological malignancies. Clonal expansion is shaped over decades by complex determinants including somatic driver gene mutations, distinct changes to DNA methylation patterns and germline genomic variants. We explored CHIP-status and DNA methylation pattern changes in blood-derived DNA, including changes with time.

Methods

Blood-derived DNA was extracted from 124 highly selected study participants at two timepoints, T1 (mean_age=72.3, ± 4.3y) and T2 (mean_age=77.1, ± 2.8y). Targeted gene panel sequencing was conducted using SureSelect XTHS2 chemistry and Illumina NextSeq 550 sequencing to determine the CHIP-status of each participant at each timepoint. Genome-wide DNA methylation (EPICv2 array) was used to generate methylation data for estimated immune cell proportions and epigenetic markers of ageing. Age- and sex-adjusted associations between CHIP-status and epigenetic markers were assessed cross-sectionally (averaged across timepoints) and longitudinally (epigenetic changes in CHIP samples from T1 to T2).

Results

Sixty-six of the 124 participants were CHIP-positive at T1 with mutations in DNMT3A (N=33), TET2 (N=32), ASXL1 (N=6), PPM1D (N=2), JAK2 (N=1), NF1 (N=1), GNB1 (N=1), and TP53 (N=2). Less than 5% of participants changed CHIP-status between timepoints. The estimated proportions of immune cells were similar in CHIP-positive and CHIP-negative participants. Most epigenetic ageing markers were higher in CHIP-positive participants cross-sectionally, with largest associations observed for PACE (per SD, β=0.50, 95%CI: 0.02-0.98, p=0.04), PhenoAge (β=0.43) and HorvathAge (β=0.42). CHIP-status was not associated with changes in any of the epigenetic markers between T1 and T2.

Conclusions

CHIP-status (positive or negative) was relatively stable over the timepoints assessed in this study. Participants with CHIP showed accelerated biological ageing compared to those without.