Background/Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the presence of somatic mutations in hematopoietic stem cells that lead to the expansion of a genetically distinct blood cell clone. CHIP is associated with increasing age, chronic inflammatory states and an elevated risk of cardiovascular events. The prevalence of CHIP mutations in healthy individuals is ~10% among those over age 65. In this study, we aimed to investigate the prevalence and mutational landscape of CHIP, as well as its association with clinical outcomes, in a large, multi-ethnic cohort of individuals with SLE.

Methods: We analyzed 1,073 individuals with SLE across four cohorts for CHIP using a hybrid capture–based targeted sequencing panel encompassing 22 canonical CHIP-associated genes, sequenced at high depth. Raw reads were aligned and processed following GATK Best Practices. Somatic mutation calling and filtering was done by GATK Mutect2 and annotated via ANNOVAR. Rigorous filters were applied to exclude potential germline mutations and artifacts. Variants were classified as exonic or deleterious mutations (defined by CADD Phred score >20). Statistical models evaluated associations between CHIP mutation status and SLE ACR classification criteria, and cardiovascular outcomes, adjusting for age, sex, disease duration, cohort and race/ethnicity.

Results: The mean age of participants was 44.7 (SD 14.4), with a disease duration of 13.2 years (SD 9.8). Exonic CHIP mutations were identified in 47% of participants, with 31% harboring deleterious CHIP mutations. The most frequently mutated genes were SETBP1 (16.3% exonic, 14% deleterious) and DNMT3A (11.4% exonic, 15.2% deleterious). The burden of deleterious CHIP mutations increased by 25.9% per decade of life (p = 0.002), and both age at diagnosis and disease duration were significantly associated with the presence of exonic (p = 0.003, p = 0.011) and deleterious mutations (p = 0.008, p = 0.019). While overall CHIP mutation status was not significantly associated with the ACR classification criteria or cardiovascular outcomes, gene-specific associations emerged. For instance, mutations in IDH1 and IDH2 were associated with hematologic involvement (p = 0.004 and p = 0.015, respectively), while mutations in KRAS and MPL were associated with a history of stroke (p = 0.008 and p = 0.02, respectively). Additionally, SETBP1, DNMT3A, ASXL1, KIT, and IDH2 showed gene-phenotype associations with renal and immunologic manifestations.

Conclusion: SLE may influence the prevalence of CHIP mutations relative to the general population, as both disease duration and age at diagnosis are important risk factors. While global CHIP status was not associated with ACR criteria, specific associations have been observed between CHIP and adverse clinical outcomes including stroke, renal and hematologic involvement. These findings highlight the need for longitudinal studies to investigate the causal role of CHIP mutations for these outcomes in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-prevalence-of-clonal-hematopoiesis-of-indeterminate-potential-chip-somatic-mutations-in-a-cohort-of-1073-sle-participants/