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

Abstract

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.

Keywords: LIFR; OSM; OSMR; atherosclerosis; cardiovascular disease; genetics; plaque.

Figure 1

Association of OSMR and LIFR variants in non-diseased arterial tissues. Per variant, the normalized expression of OSMR (A) and LIFR (B) is given in non-diseased arterial tissue. Data from GTEx Portal (www.gtexportal.org). NES: Normalized effect size. In aortic arterial tissue, rs13168867 had a NES of −0.123 and in tibial arterial tissue, rs10491509 had a NES of 0.0881 (Supplementary Figures 1, 2).

Figure 2

Association of OSMR and LIFR variants with overall plaque vulnerability. The plaques were given a vulnerability score ranging from 0 (least vulnerable) to 4 (most vulnerable). The bars represent the proportion of each plaque score per genotype for rs13168867 in the OSMR locus (A) and rs10491509 in the LIFR locus (B). The table shows the results from GTEx Portal (23) where Gene is the gene of interest; Variant is the eQTL as found in GTEx Portal, and NES refers to the normalized effect size on expression from GTEx Portal. The Alleles refer to the effect allele and the other allele in both GTEx Portal and the Athero-Express Biobank. The remaining columns in the table are referring to the analysis of these eQTLs with respect to plaque vulnerability in the Athero-Express Biobank Study. Here EAF represents effect allele frequency; Info refers to the estimated imputation score. The effect size (β) and standard error (s.e.) are relative to the effect allele; p indicates the p-value of association with plaque vulnerability of the given eQTL; Bold p: p-value of association surpasses significance threshold (p < 3.13 × 10⁻³).