Background
Sex differences are evident in the diagnosis, prognosis and etiology of atherosclerosis. Women have more stable plaques in which plaque erosion is more often a substrate for cardiovascular disease, as compared to men where plaque rupture is dominant. The extent to which these differences are correlated to DNA methylation (DNAm) in atherosclerotic plaques is not yet known.

Methods
To describe sexual dimorphic autosomal DNAm at CpG-dinucleotides (CpGs) in atherosclerotic plaques from carotid endarterectomy patients, we performed an epigenome-wide association study on sex (♀ n = 180, ♂ n = 495) corrected for age and hospital of inclusion. We applied a Bayesian method to control for latent bias and inflation. In addition, we associated genetic data with DNAm to assess the impact of genetic variation on sex differences. 

Results
After replication and meta-analysis, we identified 2,464 differentially methylated CpGs in plaques between the sexes, of which 82.0% are hypermethylated in men, not attributable to probes normalisation. Genetic analyses showed that about 80% of these CpGs are also affected by genetic variation. Furthermore, these CpGs associated with histological plaque characteristics, including intraplaque hemorrhage, vessel density and inflammation. Estrogen receptor beta was identified by Ingenuity Pathway Analysis as a potential master regulator for the sex differences found.

Conclusions
Substantial sexual dimorphic DNAm exists in plaques with males showing hypermethylation. Most of these differences were also influenced by common genetic variation and plaque composition. These data provide insight into the etiological differences between the sexes which in part may be due to DNA methylation.

07 - AUTOSOMAL SEXUAL DIMORPHISM IN METHYLATION OF ADVANCED ATHEROSCLEROTIC CAROTID PLAQUES