AUTHOR=van Keulen Danielle , van Koeverden Ian D. , Boltjes Arjan , Princen Hans M. G. , van Gool Alain J. , de Borst Gert J. , Asselbergs Folkert W. , Tempel Dennie , Pasterkamp Gerard , van der Laan Sander W. 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.658915

DOI=10.3389/fcvm.2021.658915

ISSN=2297-055X

ABSTRACT=<p><bold>Background and Aims:</bold> Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in <italic>OSM</italic> and its receptors, <italic>OSMR</italic> and <italic>LIFR</italic>, on overall plaque vulnerability, plaque phenotype, intraplaque <italic>OSMR</italic> and <italic>LIFR</italic> expression, coronary artery calcification burden and cardiovascular disease susceptibility.</p><p><bold>Methods and Results:</bold> We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased <italic>OSMR</italic> expression and that rs10491509 (A allele) was associated with increased <italic>LIFR</italic> expression in arterial tissues. No variant was significantly associated with <italic>OSM</italic> expression.</p><p>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, <italic>p</italic> = 3.00 × 10<sup>−3</sup>, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, <italic>p</italic> = 4.66 × 10<sup>−3</sup>, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, <italic>p</italic> = 6.22 × 10<sup>−3</sup>, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque <italic>OSMR</italic> expression. Neither was intraplaque <italic>OSMR</italic> expression associated with plaque vulnerability and no known <italic>OSMR</italic> eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the <italic>LIFR</italic> locus.</p><p><bold>Conclusions:</bold> 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.</p>