Analysis of CHIP-Related Mutation and Risk of Cardio-Cerebrovasculars Events in Patients with Myeloproliferative Neoplasms

Abstract

To analyze the mutant spectrum of clonal hematopoiesis of indeterminate potential (CHIP) related mutations and clinical characteristics and to explore the correlation and the possible mechanism between CHIP-related mutations and cardio-cerebrovasculars events (CCEs) in patients with myeloproliferative neoplasms (MPNs). The clinical data and next-generation sequencing results of 73 MPN patients in Beijing Anzhen Hospital from August 2019 to July 2022 were retrospectively analyzed. Statistical analyses were conducted by multivariate logistic regression for the effects of CHIP-related mutations and inflammatory cytokines on CCEs for MPNs patients. Fifty-five cases of MPN (75.3%) showed positive in CHIP-related genes. There was no significant difference in variant allele frequency of CHIP-related gene between essential thrombocythemia (ET) and polycythemia vera (PV). CHIP-related gene mutations were mainly single gene mutations, with mutation rate from high to low as JAK2V617F (63.0%, 46/73), ASXL1 (16.4%, 12/73), TET2 (11.0%, 8/73), DNMT3A (9.6%, 7/73), SRSF2 (6.9%, 5/73), SF3B1 (4.1%, 3/73), TP53(1.4%, 1/73) and PPM1D (1.4%, 1/73). The mutation rate of CHIP-related genes in MPN patients >60 years old was significantly higher than that in the patients ≤60 years old ［91.7%(33/36) vs 59.5%(22/37)］. CCEs occurred in 27 MPNs patients (37.0%, MPNs/CCEs), and 5 had recurrent CCEs, all of which were arterial events. Age (62.8±12.8 years vs 53.9±15.8 years, P =0.015), IL-1β level (17.7±26.0 vs 4.3±8.6, P =0.012), IL-8 level (360.7±598.6 vs 108.3±317.0, P =0.045), the proportion of the patients with thrombosis history (29.6% vs 2.2%, P =0.020), and the detection rate of CHIP-related mutations (88.9% vs 67.4%, P =0.040) in the group with CCEs were higher than those in the group without CCEs. Multivariate Logistic regression analysis showed that age（OR =0.917， 95%CI ：0.843-0.999, P =0.047）, thrombosis history (OR =34.148， 95%CI ：2.392-487.535, P =0.009), any CHIP-related mutations(OR =16.065， 95%CI ：1.217-212.024， P =0.035), and elevated level of IL-1β (OR =0.929， 95%CI ：0.870-0.992， P =0.027) were independent risk factors for MPNs/CCEs. CHIP-related gene mutations were not associated with CCEs in MPN patients, but DNMT3A (OR =88.717， 95%CI ：2.690-292.482， P =0.012) and ASXL1 (OR =7.941， 95%CI ：1.045-60.353， P =0.045) were independent risk factors for CCEs in PV. There is a higher mutation rate of CHIP-related genes in MPN patients, especially those over 60 years old. Older age, thrombosis history, CHIP-related mutations and IL-1β elevated levels are independent risk factors for CCEs in MPN. DNMT3A and ASXL1 mutations are independent risk factors for CCEs in PV patients. CHIP-related gene mutations and inflammatory cytokine IL-1 β elevated levels may be the novel risk factors for CCEs in MPN.