Gene-specific clonal hematopoiesis and incident dementia according to cardiovascular disease
M H Kim, P S Yang, D Kim, E Jang, H Tae Yu, T H Kim, J Park, H N Pak, B JoungAbstract
Introduction
Clonal hematopoiesis of indeterminate potential (CHIP) is a recognized risk factor for cardiovascular disease and systemic inflammation. However, its gene-specific impact on dementia and interaction with cardiovascular disease remain unclear. We investigated the association between gene-specific CHIP and incident dementia, and evaluated whether these associations differ according to cardiovascular disease.
Methods
We analyzed 494,866 participants (mean age 56.4 years) from the UK Biobank without prevalent dementia at baseline. CHIP was defined as a variant allele frequency ≥2%, and categorized according to genes (DNMT3A, TET2, ASXL1, JAK2). The study assessed the incidence of all-cause dementia, its gene-specific associations, and differential risks according to cardiovascular disease.
Results
During a median follow-up of 15.7 years (IQR 14.9–16.4), DNMT3A and ASXL1 mutations were independently associated with an increased risk of incident dementia, with adjusted hazard ratios (aHR) of 1.14 (95% confidence interval [CI] 1.03–1.27) and 1.29 (95% CI 1.04–1.60), respectively. Participants without cardiovascular disease showed a significant association between CHIP and incident dementia. In subgroup analyses, significant risks were identified in those without hypertension (aHR 1.16, 95% CI 1.00–1.35), coronary artery disease (aHR 1.15, 95% CI 1.03–1.28), or atrial fibrillation (aHR 1.16, 95% CI 1.05–1.28). However, participants with cardiovascular disease showed no statistically significant association between CHIP and dementia.
Conclusion
Clonal hematopoiesis of indeterminate potential, particularly DNMT3A and ASXL1 mutations, is an independent predictor of incident dementia. The impact of CHIP for dementia is most pronounced in individuals without major cardiovascular disease such as hypertension, coronary artery disease, or atrial fibrillation.Table 2.IR and HR for incident dementiaFigure 2.Subgroup analysis