CARS 2 Hypermethylation Is a Risk Factor for Stage B Heart Failure and Hospitalizations in the Project Baseline Health Study

The heart is a metabolically active organ with high energy demands that depend on mitochondrial oxidative phosphorylation, however as the heart begins to fail there is metabolic inflexibility and changes in mitochondrial function. Epigenetic changes such as DNA methylation can modify the transcription of genes essential for normal mitochondrial function, however this has not been studied in Stage B or pre-heart failure (HF). In 752 participants from the Project Baseline Health Study, we tested differences in DNA methylation in mitochondrial-related genes for association with Stage B HF compared to Stage A (at-risk for HF). We then validated these findings in 918 participants from the CATHGEN study for risk of incident HF hospitalization. One region on chromosome 13 overlapping with the cysteinyl-tRNA synthetase 2 ( CARS2 ) gene, containing five cytosine-phosphate-guanine (CpG) probes, was significantly associated with a small mean regional increase in DNA methylation in Stage B HF (0.63%, Stouffer p=0.005). In CATHGEN, one CARS2 probe, cg08289839, was significantly associated with time-to-incident HF hospitalization (adjusted HR 1.74 [95% CI 1.18-2.56], FDR p=0.02). In this study of epigenetic changes of mitochondrial genes, these results indicate that CARS2 DNAm may play a role in HF pathogenesis and should be studied in future HF research.