JAK2V617Fmutation is highly prevalent in patients with ischemic stroke: a case-control study

Abstract

Ischemic stroke has a high recurrence rate despite treatment. This underlines the significance of investigating new possible cerebrovascular risk factors, such as the acquired gene mutation JAK2V617F found in 3.1% of the general population. We aimed to investigate the prevalence of the JAK2V617F mutation in an ischemic stroke population compared with matched controls. We enrolled 538 consecutive Danish patients with ischemic stroke (mean age 69.5± 10.9, 39.2% female) within seven days of symptom onset. Using multiple adjusted conditional logistic regression analysis, we compared the prevalence of JAK2V617F with age- and sex-matched controls free of ischemic cerebrovascular disease (ICVD) from the Danish General Suburban Population Study. DNA was analyzed for the JAK2V617F mutation using sensitive droplet digital PCR in patients and controls. Of the 538 patients with ischemic stroke, 61 (11.3%) had the JAK2V617F mutation. There were no differences in patient demographics or cerebrovascular comorbidities between patients with and without mutations. Patients with ischemic stroke were more likely to have the JAK2V617F mutation compared with matched controls in whom the JAK2V617F prevalence was 4.4%% (odds ratio (OR)=2.37, 95% CI [1.57, 3.58], p<0.001). A subanalysis stratified by smoking history revealed that the association was strongest in current smokers (OR=4.78, 95% CI [2.22, 10.28], p<0.001). Patients with ischemic stroke are 2.4 times more likely to have the JAK2V617F mutation than matched controls without ICVD when adjusting for other cerebrovascular risk factors. This finding supports the JAK2V617F mutation as a novel cerebrovascular risk factor.

Concerns regarding myelofibrosis-type megakaryocyte dysplasia

“…These SVTs have been found to precede the diagnosis of MPNs and have also been associated with clonal hematopoiesis of indeterminate potential (CHIP) by DNMT3A mutations [ 4 , 5 ]. Additionally, JAK2V617F -mutated CHIP has been observed in individuals with arterial thrombosis, such as ischemic stroke [ 6 ]. It is possible that CHIP may progressively expand over time and eventually develop into overt MPNs.…”

Are the available data sufficient to suggest cytoreductive agents for patients with CHIP and stroke?

“…Notably, in previous studies the frequency of the clonal hematopoiesis of undetermined significance (CHIP) JAK2 V617 mutation defined as the presence of a variant allele fraction (VAF) ≥2% was much lower than that now reported, being 0.17% among 1152 patients with IS. 2 In the study of Kristiansen et al, 1 75% of the carriers of JAK2 V617F had a VAF <1%, suggesting that the mutation is associated with a severe vascular event even with very low VAF values.…”

“…We were intrigued by the recent publication from Kristiansen et al 1 in Blood Advances , which presents findings regarding the prevalence of the JAK2 V617F mutation in patients with ischemic stroke (IS). Using a case-control design with 538 IS cases and 1613 age- and sex-matched controls free of ischemic cerebrovascular disease, the study unveiled a statistically significant disparity in the occurrence of this somatic mutation.…”

CHIP-JAK2V617F, chronic inflammation, abnormal megakaryocyte morphology, organ failure, and multimorbidties

“…Thank you so much for giving us the opportunity to comment on the commentary by Barosi et al titled “ JAK2V617F and ischemic stroke: CHIP or CMD-NBV?” 1 regarding our recent article published in Blood Advances . 2 Barosi et al underscore several highly important features of JAK2V617F -associated clonal hematopoiesis of indeterminate potential (CHIP), including the increased risk of cardiovascular diseases and higher frequency of splanchnic vein thrombosis. They also underscore common knowledge that JAK2V617F encodes a constitutively activated tyrosine kinase in the STAT signaling pathway, which gives rise to myeloproliferation and a chronic inflammatory state.…”

“…In the context of the above considerations, implying a paradigm shift in the diagnosis and treatment of MPNs, sooner better than later, by screening of patients with a high risk of having MPN, such as patients with ischemic stroke or other cardiovascular diseases alluded to above, there is an urgent need for an interdisciplinary collaboration between hematologists, neurologists, cardiologists, and others caring for patients with chronic inflammatory diseases at risk of harboring the JAK2V617F mutation. We have proposed that the optimal platform for such a collaboration is a CHIP clinic, 2 where follow-up programs are designed for citizens and patients positive for CHIP- JAK2V617F . Thereby, we start a new era of preventive medicine by much earlier diagnosis of MPN and much earlier treatment with stem-cell–targeting therapy with IFN.…”