TET2-mutant clonal hematopoiesis is associated with peripheral bypass graft occlusion: a multicenter retrospective cohort pilot study

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Objective Clonal hematopoiesis of indeterminate potential (CHIP), defined by somatic mutations in hematopoietic cells, is associated with cardiovascular disease through proinflammatory mechanisms. We investigated whether CHIP, and specifically TET2 mutations, are associated with peripheral bypass graft occlusion in patients with peripheral arterial disease (PAD). Methods In this multicenter retrospective cohort pilot study, 47 PAD patients who had undergone femoropopliteal or femorocrural bypass grafting were analyzed. CHIP status was assessed from peripheral blood using a 40-gene myeloid sequencing panel. Time-to-event analyses were performed using Kaplan–Meier survival analysis and multivariable Cox proportional hazards regression adjusted for diabetes and smoking status. Results Of 47 patients, 33 had bypass graft occlusion and 14 had patent grafts. CHIP was detected in 14 individuals (29.8%). The mutational spectrum differed markedly between groups: in the patent graft group, all CHIP mutations involved DNMT3A exclusively, whereas TET2 was the most frequently mutated gene in the occlusion group (7/17 mutations; 41%). All five TET2 -mutant patients belonged to the occlusion group. Cell sorting revealed CHIP variants predominantly in myeloid cells, NK cells, and B lymphocytes, with near-absence in T cells. Cox regression demonstrated a significant association between TET2 mutation and bypass occlusion (HR=6.70; 95% CI: 1.96–22.96; P=0.003). Conclusions TET2 mutations are associated with peripheral bypass graft occlusion and may represent a novel biomarker for graft failure risk. These findings require validation in larger prospective studies.