부산대학교 도서관

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon characterized by the presence of clonal populations of hematopoietic-derived cells in whole blood that harbor functional leukemogenic somatic mutations. Despite the well-established associations between aging and CHIP and aging and genome-wide DNA methylation (DNAm), the association between CHIP and changes in DNAm remains to be fully elucidated. To fill this knowledge gap, an epigenome-wide association study of CHIP was performed in Framingham Heart Study participants from the Offspring cohort (ntotal = 1594; 54% women; mean age 67 years) using whole blood derived DNA to elucidate the DNAm profiles of any CHIP and the three most frequently mutated CHIP driver genes DNMT3A, TET2, and ASXL1/2. Linear mixed models were used to test associations between CHIP status as the predictor variable and genome-wide DNAm of CpG sites as the outcome, with adjustment for age, age, sex, smoking, 33 surrogate variables, and familial relatedness. From the analysis, 189 CpGs were found to be associated with any CHIP, and 139, 107, and 4 were associated with DNMT3A, TET2, and ASXL1/2 CHIP, respectively (Bonferroni corrected P<1х10). The CpGs associated with the DNMT3A, TET2, and ASXL1/2 CHIP were distinct. Genome-wide DNAm directions of effect were similar for DNMT3A and ASXL1/2 CHIP but opposite to TET2. Gene expression analysis identified CpG-gene transcript pairs for any CHIP and CHIP subtypes. The most significant gene sets were enriched in pathways related to immune response and hematopoietic cell lineage. Two-sample Mendelian randomization analysis was additionally conducted to investigate whether methylation at CHIP-associated CpGs causally influences risk of cardiometabolic traits and all-cause mortality. Evidence of a putative causal role of CHIP-associated CpGs in relation to several traits, including BMI and hypertension, and all-cause mortality was found. Taken together, we identified CpGs associated with CHIP and with the three major CHIP driver genes, elucidated their methylomic signatures, identified CpG-transcript pairs, and provided support for a potential causal role of CHIP-associated CpGs in relation to cardiometabolic traits and all-cause mortality.