Clonal Hematopoiesis of Indeterminate Potential Linked to Higher Risk of Stroke
Key findings
- Clonal hematopoiesis of indeterminate potential (CHIP) is a recently identified risk factor for cardiovascular disease. This study of stroke risk with CHIP, the first to distinguish between subtypes of stroke, examined genomic data on 86,178 participants in prospective cohort studies and biobanks
- CHIP was associated with increased risk of incident stroke (HR, 1.14; P=0.01), primarily driven by an increased risk of hemorrhagic stroke (HR, 1.24; P=0.04)
- Mutation of TET2 increased the risk of total stroke (HR, 1.85; P=0.004) and ischemic stroke (HR, 1.93; (P=0.006), and mutation of DMNT3A increased the risk of hemorrhagic stroke (HR, 1.44; P=0.03)
- While CHIP has been previously associated with atherosclerotic disease, the finding that CHIP is more strongly associated with hemorrhagic stroke was unexpected and is prompting further investigation
- CHIP and inflammatory dysregulation may play a larger role in both ischemic and hemorrhagic stroke than previously known. Future risk stratification and therapeutic developments should bear this in mind
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition in which somatic gene mutations accumulate in hematopoietic stem cells in asymptomatic adults. First described in 2014, CHIP is common, affecting 10%–20% of people over age 70, and increases the risk of hematologic malignancies.
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More recently, it's been established that CHIP also increases the risk of coronary heart disease and cardiovascular disease–related mortality, independently of traditional risk factors.
Researchers at Massachusetts General Hospital recently confirmed that CHIP is associated with an increased risk of stroke and determined the effect size depends on stroke subtype and the specific gene variant. Romit Bhattacharya, MD, instructor in Medicine, Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center and investigator in the Cardiovascular Research Center at Mass General, and colleagues detail the findings in Stroke.
Methods
The researchers obtained genome sequence data on 86,178 individuals participating in the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, Women's Health Initiative, UK Biobank or Mass General Brigham Biobank.
At baseline, the mean age of each cohort ranged from 46.5 to 73.9 years, and the overall prevalence of CHIP was 6%. During follow-up, 7,426 individuals had a first stroke.
CHIP and Incident Stroke
When the data were meta-analyzed and adjusted for age, race and sex, the associations between any CHIP mutation and stroke were:
- Total stroke—HR, 1.14 (P=0.01)
- Hemorrhagic stroke—HR, 1.24 (P=0.04)
- Ischemic stroke—HR, 1.11 (P=0.10)
Individual CHIP Genes and Stroke Risk
As in previous research, the most common CHIP-related genes were DNMT3A, TET2, ASXL1 and JAK2. The team found significant associations between:
- TET2 and total stroke—HR, 1.85 (P=0.004)
- TET2 and ischemic stroke—HR, 1.93 (P=0.006)
- DMNT3A and hemorrhagic stroke—HR, 1.44 (P=0.03)
CHIP and Stroke Subtypes
The researchers performed sensitivity analyses in the Women's Health Initiative cohort, which had the greatest number of strokes (n=4,607):
- Ischemic stroke—CHIP was significantly associated with small-vessel stroke (HR, 1.55; P=0.001) and not with large-artery stroke or cardioembolic stroke
- Hemorrhagic stroke subtypes—CHIP was significantly associated with subarachnoid hemorrhage (HR, 1.98; P=0.004) and not with intracerebral hemorrhage
In the Mass General Brigham Biobank cohort, several cerebrovascular events were significantly more common in individuals with CHIP than those without:
- Cerebral aneurysm—2.9% vs. 1.6% (P=0.001)
- SAH—0.76% vs. 2.3% (P=0.02)
- Nontraumatic SAH—2.3% vs. 1.0% (P=0.003)
Applying the Findings
CHIP and inflammatory dysregulation may play a larger role in both ischemic and hemorrhagic stroke than previously known. Future risk stratification and therapeutic developments should bear this in mind.
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