Increased Risk of Stroke Observed in Individuals With Clonal Hematopoiesis

Author(s):

Even after adjusting to traditional stroke risk factors, the associations between clonal hematopoiesis and all stroke types, ischemic stroke, and hemorrhagic stroke remained significant.

Romit Bhattacharya, MD

Investigators have identified clonal hematopoiesis of indeterminate potential (CHIP), a novel age-related risk factor for cardiovascular disease-related morbidity and mortality, as a high-risk factor for stroke, particularly hemorrhagic and small vessel ischemic stroke.

A total of 78,752 individuals from 8 prospective cohorts who had plasma genome sequencing data of blood DNA were analyzed to assess the role of CHIP as a risk factor for all stroke types. Led by Romit Bhattacharya, MD, cardiology fellow, Massachusetts General Hospital, the study also further examined CHIP-stroke associations according to commonly mutated CHIP genes (DNMT3A, TET2, and ASXL1).

Among those individuals included, 7426 (8.6%) incident stroke cases were recorded, with participants having a mean age ranging from 46.5 to 73.9 years. In the fixed-effects meta-analysis, any CHIP mutation was found to be associated with an increased risk of total stroke (HR, 1.14 [95% CI, 1.03-1.27]; P = .01) after adjusting for age, race, and sex. To the surprise of the authors, the risk estimate for CHIP association was numerically greater for hemorrhagic (HR, 1.24 [95% CI, 1.01-1.51]; P = .04) than ischemic stroke (HR, 1.11 [95% CI, 0.98-1.25]; P = .10), although tests for heterogeneity were negative (P heterogeneity, 0.34).

Bhattacharya et al concluded that, "The finding that CHIP was consistently and strongly associated with hemorrhagic stroke raises questions that require further investigation regarding the role of CHIP in vascular fragility and the formation of saccular intracranial aneurysms."

When restricting analysis to just those with a variant allele fraction greater than 10%, the associations with total stroke (HR, 1.18 [95% CI, 1.05-1.33]; P <.01), ischemic stroke (HR, 1.14 [95% CI, 0.99-1.30]; P = .07) and hemorrhagic stroke (HR, 1.28 [95% CI, 1.03-1.61]; P = .03) were not appreciably altered.

Individual gene analysis suggested that TET2 may be selectively associated with ischemic stroke. Chip driver mutations were identified in carriers of DNMT3A (535 of 45,091 [1.2%]), TET2 (212 of 45,091 [0.5%]), ASXL1 (64 of 45091 [0.1%]), JAK2 (39 of 45,091 [<.01%]), and TP53 (16 of 45,091 [<.01%]); however, only the TET2 gene had a significant association with total stroke (HR, 1.85; P = .004).

An analysis separating ischemic and hemorrhagic stroke identified TET2 as an increased risk for ischemic stroke (HR, 1.93; P = .006), while effect sizes for the association of TET2 (HR, 1.50; P = .15) and DMNT3A (HR, 1.44; P = .03) with hemorrhagic stroke were similar.

After adjusting for covariates such as age, sex, smoking, history of diabetes, history of hypertension, and the first 10 principal components of genetic ancestry, there was no appreciable change in the associations of CHIP and all stroke (HR, 1.23 [95% CI, 1.02-1.48]; P = .03), ischemic stroke (HR, 1.21 [95% CI, 0.98-1.49]; P = .08), or hemorrhagic stroke (HR, 1.41 [95% CI, 1.09-1.83]; P <.01). These findings indicated that CHIP-stroke associations are independent of traditional stroke factors.

Ischemic stroke cases in Cardiovascular Health Study, Multi-Ethnic Study of Atherosclerosis, and Women’s Health Initiative (WHI) studies were further divided into cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS). According to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtype CHIP was significantly associated with SVS (HR, 1.55; P = .001), and not LAS (HR, 1.12; P = .62) or CES (HR, 1.05; P = .68) subtypes in WHI. Furthermore, with regard to hemorrhagic subtypes in WHI, investigators found a stronger association between CHIP and SAH (HR, 1.98; P = .004) than with intracerebral hemorrhage (HR, 1.31; P = .063).

REFERENCE

Bhattacharya R, Zekavat SM, Haessler J, et al. Clonal hematopoiesis is associated with higher risk of stroke. Stroke. Published online November 8, 2021. doi:10.1161/STROKEAHA.121.037388