TET2 mutations in myeloproliferative neoplasms: potential mediation of atrial fibrillation by interleukin-1β and impact on stroke risk in clinical cohorts

Background The role of clonal hematopoiesis of indeterminate potential (CHIP) related gene mutations in atrial fibrillation (AF) and stroke in patients with myeloproliferative neoplasms (MPNs) remains insufficiently investigated. Objectives To investigate the role of CHIP related gene mutations in AF and stroke in patients with MPNs and explore the role of cytokines. Methods A retrospective cohort of 465 MPN patients (mean age 61; range, 10-89; 49% male) and an additional validation cohort ( n = 196) were analyzed using multivariable Cox regression, Firth-corrected Cox regression, and competing risks models, adjusting for confounders. Propensity score matching (PSM) balanced confounders. Mediation analysis assessed the role of IL-1β in the link between TET2 and AF/stroke. Results CHIP-related mutations increased the risk of AF in all 3 models, both before and after PSM. TET2 independently increased the risk of AF (Cox, hazard ratio [HR] = 3.13; 95% CI, 1.62, 6.06; P = .001; Firth, HR = 3.03; 95% CI, 1.55, 5.74; P = .002; Fine-Gray, subdistribution HR = 2.98; 95% CI, 1.46, 6.08; P = .003). Sensitivity analysis in the JAK2 subgroup and PSM cohort, as well as the validation cohort, all confirmed that TET2 remained associated with AF (all P < .05). Interleukin (IL)-1β partially mediated the association between TET2 and AF ( P = .034). AF predicted the occurrence of stroke ( P < .05) and partially mediated the relationship between TET2 and stroke. No direct association between CHIP/ TET2 and stroke was observed, and IL-1β did not play a role in the association between TET2 and stroke. Conclusion TET2 mutations increase the risk of AF, which may be associated with the IL-1β-mediated inflammatory pathway. AF serves as a critical intermediary for CHIP-associated ischemic stroke. Integrating TET2 status into AF surveillance and anticoagulation strategies may reduce thrombosis.