Pharmacoepigenomic effects of anti-hypertensive drugs on DNA methylation and its implication to drug response and side effects

Antihypertensives are often prescribed in a ‘trial and error’ mode in management of hypertension. Significant drug response variability for these antihypertensives affects the therapeutic efficacy and increases the chance of developing adverse reactions. The study aims to investigate the influence of antihypertensives on the DNA methylation and its possible role in drug response variability and adverse events. The study evaluated the expression level of epigenetic genes, global DNA methylation, hydroxy-methylation level, and gene level differential methylation in in-vitro system post antihypertensive treatment. The epigenetic gene expression pattern upon amlodipine, enalapril, telmisartan, and metoprolol treatment indicated a drug, dosage, and duration-dependent expression of DNMTs and TETs. Global methylation and hydroxy-methylation patterns overlap with the gene expression patterns of DNMTs and TETs for amlodipine and telmisartan, but variability was observed with metoprolol and enalapril. Gene-specific methylation pattern revealed several drug and duration-specific differential methylated genes, which can potentially impact therapeutic outcomes and adverse events as evidenced by their HPO terms. The study signifies that antihypertensives influence the methylation pattern and drug-induced differential methylation of certain genes which can potentially contribute to adverse effects while that in other genes may have therapeutic utility for other diseases. Hypertension is usually treated with medicines called antihypertensive drugs. All patients do not respond to these medicines in the same way – some may have better results than others, or develop side effects. This difference is partly due to our genes, but other factors, called epigenetic changes, can also play a role. DNA methylation is an epigenetic change that refers to the molecular changes to DNA that can turn genes on or off without altering the DNA sequence. In our study, we looked at how four commonly used antihypertensive medicines – amlodipine, enalapril, telmisartan, and metoprolol can impact DNA methylation. We measured the activity of certain “DNAmodifying” enzymes involved in DNA methylation and also looked for patterns of DNA methylation at whole genome level. We found that each of these antihypertensives can change the methylation patterns in different ways which are duration and dose dependent. Some of the affected genes have been linked to treatment of hypertension or related conditions while others also reflect on drug side effects.