Aurora Semerano, MD
Bhattacharya R, Zekavat SM, Haessler J, Fornage M, Raffield L, Uddin MM, Bick AG, Niroula A, Yu B, Gibson C, et al. Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. Stroke. 2021.
Clonal hematopoiesis of indeterminate potential (CHIP) consists of a clonal expansion of circulating blood cells that arises from somatic mutations in hematopoietic stem cells. This condition usually does not entail abnormal blood cell counts and is common in older individuals, since it has been detected by DNA sequencing in >10% of people aged 70+ years. While carrying a relatively modest risk of developing hematological malignancy, from 2014 onwards CHIP has been unexpectedly and increasingly recognized as an independent, non-traditional risk factor for cardiovascular diseases and atherosclerosis, underlying the important interplay between aging, inflammation, and cardiovascular health. Interestingly, CHIP is determined by mutations in a handful of genes, which are currently under active investigations in experimental models. For example, accelerated atherosclerosis and increased release of inflammatory cytokines have been found in mice that bear TET2-deficient leukocytes. The relationship between CHIP and stroke risk was first reported in 2014 by Jaiswal et al.1 Indeed, by analyzing two cohorts of ~3000 patients, the presence of a somatic mutation was associated with an increased risk of ischemic stroke with a hazard ratio of 2.6 (95% CI, 1.4 to 4.8).
In the article by Bhattacharya et al. recently published in Stroke, the authors aimed at expanding the knowledge about the association between CHIP and risk of cerebrovascular events, taking into account both ischemic and hemorrhagic strokes, as well as stroke etiology. A total of 86,178 individuals from 8 prospective cohorts or biobanks were included. The overall prevalence of CHIP at baseline was 6%. CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14; 95% CI, 1.03–1.27). Unexpectedly, this relationship was primarily driven by a 24% increased odds of hemorrhagic stroke, particularly subarachnoid hemorrhage. Though CHIP was not found to be associated with ischemic stroke overall, in exploratory analyses from one female patient cohort, CHIP was more strongly associated with small vessel disease than with large artery atherosclerosis or cardioembolic etiologies. When analyzing mutations in specific CHIP genes, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke.