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The association between oxidative stress and coronary artery disease (CAD) is well documented. However, the role of epigenetic factors contributing to oxidative stress is relatively unexplored. In this study, we aimed to explore the impact of DNA methylation profile in BCL2/E1B adenovirus interacting protein 3 (BNIP3), extracellular superoxide dismutase (EC-SOD) and glutathione-S-transferase P1 (GSTP1) on the oxidative stress in CAD. Further, the contribution of folate pathway genetic polymorphisms in regulating epigenome was elucidated. The expression of BNIP3, EC-SOD, and GSTP1 were studied by using Maxima@SYBR-green based real-time qPCR approach in peripheral blood samples. Combined bisulfite restriction analysis and methylation-specific PCR were used to study promoter CpG island methylation. Further, the effect of homocysteine on BNIP3 gene expression was studied in human aortic endothelial cells in vitro. CAD cases exhibited upregulation of BNIP3, downregulation of EC-SOD and GSTP1. Hypomethylation of BNIP3 and hypermethylation of EC-SOD were observed in CAD cases. The expression of BNIP3 was positively correlated with homocysteine, MDA, protein carbonyls, and methylene tetrahydrofolate reductase C677T, while showing inverse association with cytosolic serine hydroxymethyl transferase C1420T. The expressions of EC-SOD and GSTP1 showed positive association with thymidylate synthase (TYMS) 2R3R, while inverse association with MDA, protein carbonyls, and methionine synthase reductase (MTRR) A66G. In vitro analysis showed homocysteine-dependent upregulation of BNIP3. The results of this study suggest that the aberrations in one-carbon metabolism appear to induce altered gene expression of EC-SOD, GSTP1, and BNIP3, and thus contribute to the increased oxidative stress and increased susceptibility to CAD.

Dietary folate status and TYMS 5'-UTR 28bp tandem repeat polymorphism are important effect modifiers of CAD risk associated with genetic variants in remethylating genes.

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.