Introduction:
Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations lead to hematopoietic malignancy. Accumulating evidence suggest that CHIP-related mutations contribute to development of atherosclerosis. However, the prevalence and gene mutational discrepancy in patients with non-ischemic dilated (DCM) or ischemic cardiomyopathy (ICM) is unclear. In this study, we aim to examine the incidence and clinical significance of CHIP-related mutations in DCM and ICM patients.
Methods:
Forty-eight ICM and 52 DCM patients were recruited through the Heart Failure Registry at the University Hospital Jena (ICM vs. DCM: median age: 69 vs. 62 years; BMI: 27.7 ±3.8 vs. 28.5 ±5.2 kg/m2; NYHA: 2.4±0.7 vs. 2.2 ±0.7; LVEF: 40.4±13.5 vs. 36.8±12.3; p=not significant). Genomic DNA (gDNA) was isolated from peripheral blood and next-generation sequencing was performed with the TruSight Myeloid Sequencing Panel using the MiniSeq™ System (Illumina). Data was analyzed using VariantStudio™ 3.0 (Illumina). Somatic mutation was confirmed with 4 bioinformatics tools (SIFT, PolyPhen-2, FATHMM and Mutation Taster) and gDNA from buccal swab when it was available.
Results:
Sequencing was performed with a sensitivity of variant allele frequency at 0.05 and a read depth ≥ 500. CHIP-associated single somatic mutation is found in 18 patients and the overall CHIP incidence in DCM and ICM was 23% and 13%, respectively. The CHIP-related mutations were age-dependent in the ICM cohort; however, such age-dependent change in mutation frequency was not observed in the DCM patients. Among all mutations identified, DNMT3A was the most commonly mutated gene and its mutation was identified in 39% of total patients analyzed. Additional common mutations that were detected included TET2 and CUX1. Following a median 3.9 years of tracking, hazard-risk model analysis revealed that the commonly mutated genes identified were associated with increased risk of adverse clinical outcome in the DCM cohort (HR=4.65, 95%CI=1.11-19.52, p=0.0356). Nevertheless, such association was not significant in the ICM patients (HR=1.19, 95%CI=0.15-9.56).
Conclusion:
CHIP-associated somatic mutations are identified in both ICM and DCM patients. Furthermore, the mutation rate is higher in DCM patients and it is independent of age. Among all the mutated CHIP-associated genes analyzed, DNMT3A remains to be the most commonly mutated gene, and followed by TET2 and CUX1. Furthermore, these commonly mutated CHIP-associated genes render increased risk of adverse clinical events in the DCM cohort. Further examinations will be necessary to delineate the underlying mechanism of how CHIP mutations contributes to DCM.