Abstract 197: Statin Therapy Is Associated With Higher MTHFR Methylation Levels in a Stroke Cohort
Introduction: Epigenetics refers to changes in gene function that occur by gene methylation, histone modification or RNA mechanisms. Many of these are heritable, but can also be altered by lifestyle and medication. Genome-wide hypomethylation is associated with atherosclerosis and hyperhomocysteinemia, and specific genes can be hyper or hypomethylated in vascular disease. Statins have pleiotropic effects on the vasculature, and may affect DNA methylation.
Hypothesis: The methylation levels of genes implicated in vascular disease are altered by treatment with common cardiovascular medications.
Methods: 189 individuals from a well characterised stroke cohort and controls were included. 44 were established on statin therapy, 49 on aspirin and 28 on an ACE inhibitor. The following genes implicated in vascular disease were investigated: LINE1, SOD3, ALOX15, ERa, MTHFR, PITX2, IFNGR1, TNFa, IL10, and INS. Methylation status was assessed by bisulphite conversion of DNA followed by PCR and pyrosequencing. Each methylation site was analysed individually and mean methylation level across all sites within a gene calculated. Statistical analysis for the effect of drug therapy was based on logistic regression and ANOVA.
Results: One significant association was found: subjects on statin therapy had higher MTHFR methylation levels than those not receiving statin (p=0.002). Statistical analysis adjusted for stroke effect (p=0.025) remained significant. Correction for multiple testing was not performed as the candidate genes are linked in pathways. There was no effect of aspirin or ACE inhibitor on methylation status of any of the genes tested.
Discussion: MTHFR plays an important role in homocysteine and folate metabolism, providing methyl groups for DNA methylation. High levels of homocysteine are a risk factor for cardiovascular disease and there is published evidence that statin therapy results in lower plasma homocysteine levels. This finding requires further investigation in a larger cohort with a defined dose and duration of treatment. If this finding is replicated, there may be value in exploring the mechanisms linking statins, MTHFR methylation and homocysteine levels and the implications for primary and secondary prevention of vascular events.
Author Disclosures: M. MacLeod: None. O. Pogoryelova: None. G. Horgan: None. P. Haggarty: None.
- © 2015 by American Heart Association, Inc.