Common Variants Associated With OSMR Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans

Background and Aims: Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility. Methods and Results: We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression. We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00 × 10−3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66 × 10−3, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, p = 6.22 × 10−3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus. Conclusions: Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility

Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions

Background: Tobacco smoking is a major risk factor for atherosclerotic disease and has been associated with DNA methylation (DNAm) changes in blood cells. However, whether smoking influences DNAm in the diseased vascular wall is unknown but may prove crucial in understanding the pathophysiology of atherosclerosis. In this study, we associated current tobacco smoking to epigenome-wide DNAm in atherosclerotic plaques from patients undergoing carotid endarterectomy. Methods: DNAm at commonly methylated sites (cytosine-guanine nucleotide pairs separated by a phospho-group [CpGs]) was assessed in atherosclerotic plaque samples and peripheral blood samples from 485 carotid endarterectomy patients. We tested the association of current tobacco smoking with DNAm corrected for age and sex. To control for bias and inflation because of cellular heterogeneity, we applied a Bayesian method to estimate an empirical null distribution as implemented by the R package bacon. Replication of the smoking-associated methylated CpGs in atherosclerotic plaques was executed in the second sample of 190 carotid endarterectomy patients, and results were meta-analyzed using a fixed-effects model. Results: Tobacco smoking was significantly associated to differential DNAm in atherosclerotic lesions of 4 CpGs (false discovery rate <0.05) mapped to 2 different genes (AHRR, ITPK1) and 17 CpGs mapped to 8 genes and RNAs in blood. The strongest associations were found for CpGs mapped to the gene AHRR, a repressor of the aryl hydrocarbon receptor transcription factor involved in xenobiotic detoxification. One of these methylated CpGs were found to be regulated by local genetic variation. Conclusions: The risk factor tobacco smoking associates with DNAm at multiple loci in carotid atherosclerotic lesions. These observations support further investigation of the relationship between risk factors and epigenetic regulation in atherosclerotic disease