Journal of thrombosis and haemostasis : JTH · 2025
TET2 mutations in myeloproliferative neoplasms: potential mediation of atrial fibrillation by interleukin-1β and impact on stroke risk in clinical cohorts.
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Teng Guangshuai, Duan Minghui, Shang Ke, Zhang Yuhui, Wei Xiaojing, Peng Lan, Tse Gary, Zhou Yuan, Lip Gregory Y H, Liu Tong, Bai Jie
Аннотация
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.
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.