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Clonal hematopoiesis with DNMT3A mutation is associated with lower white matter hyperintensity volume
Woo-Jin Lee1,2, Keun-Hwa Jung2, Han Song3
1Department of Neurology, Seoul National University Bundang Hospital, Seongnam-si, South Korea.
CNS Neuroscience & Therapeutics
|February 22, 2023
Summary
Clonal hematopoiesis (CHIP) with DNMT3A mutation is linked to reduced white matter hyperintensity (WMH) volume in the brain. This suggests a potential protective role for CHIP with DNMT3A mutation in endothelial damage.
Area of Science:
- Hematology
- Neurology
- Genetics
Background:
- Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for cerebrovascular events.
- The association between CHIP and cerebral white matter hyperintensity (WMH) severity has not been previously established.
- This study investigates the impact of CHIP and its primary driver mutations on WMH.
Purpose of the Study:
- To evaluate the effect of CHIP and its major driving mutations on the severity of cerebral white matter hyperintensity (WMH).
- To determine if specific CHIP mutations, particularly DNMT3A, are associated with WMH volume.
- To explore the potential protective role of CHIP with DNMT3A mutation in the context of WMH.
Main Methods:
- Analysis of a cohort of 964 individuals aged ≥50 years undergoing routine health check-ups with available DNA repositories and brain MRI.
- Classification of subjects into CHIP-positive and CHIP-negative groups, identifying major driving mutations (DNMT3A, TET2, ASXL1).
- Linear regression models were used to assess the association between CHIP, its mutations, and WMH volume (total, periventricular, subcortical), adjusting for cardiovascular risk factors.
Main Results:
- Out of 964 subjects, 160 were CHIP positive, with DNMT3A mutations being the most frequent (48.8%).
- CHIP, specifically with DNMT3A mutation, was associated with lower total WMH volume, contrary to other CHIP mutations.
- Higher variant allele fraction (VAF) of DNMT3A mutations correlated with reduced total and periventricular WMH volumes, but not subcortical WMH.
Conclusions:
- Clonal hematopoiesis with DNMT3A mutation is quantitatively linked to a reduced volume of cerebral WMH, particularly in the periventricular regions.
- CHIP characterized by DNMT3A mutation may exert a protective effect against the endothelial pathomechanisms underlying WMH.
- These findings highlight a specific genetic influence on cerebrovascular pathology within the context of CHIP.
