Prevalence and impact of additional CHIP mutations in JAK2V617F-positive ischaemic cerebrovascular patients

The JAK2V617F mutation is associated with increased cardiovascular risk, including ischaemic stroke. This study investigates the prevalence of additional mutations in ischaemic cerebrovascular patients with and without JAK2V617F to better understand the mechanisms contributing to thrombotic risk. We examined 63 patients with the JAK2V617F mutation and 126 matched controls from a cohort of 591 ischaemic cerebrovascular patients. Somatic mutations were assessed using targeted next-generation sequencing (NGS). Serum thromboinflammatory markers were evaluated in a subset of patients. Additional somatic mutations were more common in JAK2V617F-positive patients than in controls (47.6% vs. 30.2%, p = 0.028). Patients with JAK2V617F had a higher prevalence of other mutations with variant allele frequencies (VAFs) above 10% (23.8% vs. 7.9%, p = 0.005), a pattern that persisted in cases with JAK2V617F <1% (p = 0.019). In JAK2V617F-positive patients, additional somatic mutations were associated with higher monocyte levels, even when excluding myeloproliferative neoplasms patients (p = 0.011). Patients with other clonal haematopoiesis of indeterminate potential mutations exhibited higher vascular cell adhesion molecule 1 (p = 0.027), soluble urokinase plasminogen activator receptor (p = 0.010) and IL-10 (p = 0.045), as well as higher neutrophil to lymphocyte ratio (p = 0.002). Ischaemic cerebrovascular patients with the JAK2V617F mutation more frequently harbour other somatic mutations and at higher VAF. This may reflect a more advanced clonal profile with relevance for vascular risk in JAK2V617F-positive individuals.