Pasterkamp, G. | Search bioRxiv

bioRxiv2019

Polygenic Susceptibility of Aortic Aneurysms Associates to the Diameter of the Aneurysm Sac: the Aneurysm-Express Biobank Cohort.

PurposeAbdominal aortic aneurysms (AAA) have a multifactorial pathology with both genetic and environmental risk factors. Recent genome-wide association studies (GWAS) have discovered ten genetic risk loci for AAA. To what extent these genetic loci contribute to the aneurysm pathology is yet unknown. This study aims to investigate whether genetic risk variants are associated with three clinical features: diameter of aneurysm sac, type of artery and symptoms.\n\nMethodsWe used aneurysm tissue from 415 patients included within the Aneurysm-Express biobank. A best fit polygenic risk score (PRS) based on previous GWAS effect size estimates was modeled for each clinical parameter by comparing model predictions across different p-value thresholds. Next, the established 10 risk variants for AAA were tested individually for association with selected clinical phenotypes. Models were corrected for age, sex, ancestral background, smoking status and diameter of the aneurysm sac or artery type if applicable, and data was normalized.\n\nResultsThe best fit PRS (including 272 SNPs with PT=0.01015) showed a significant correlation with diameter of the aneurysm sac (R2 = 0.019, p = 0.001). No association was found with clinical symptoms or type of artery. Individual variant analysis showed no clear associations with any of the clinical features.\n\nConclusionsWithin the Aneurysm-Express Biobank Study, a weighted polygenic score of AAA susceptibility explained 1.9% of the phenotypic variation (p = 0.001) in aneurysm diameter. Individual risk variant analysis showed no clear associations. Given our limited sample size, future biobank collaborations need to confirm a potential causal role of individual SNPs on the pathology of aneurysms.

genetics↗

bioRxiv2019

Common variants in OSMR contribute to carotid plaque vulnerability

Background and aimsOncostatin 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 resultsWe 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 ({beta}=0.118 {+/-} s.e.=0.040, p=3.00x10-3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat ({beta}=0.248 {+/-} s.e.=0.088, p=4.66 x 10-3, C allele) and collagen content ({beta}=-0.259 {+/-} s.e.=0.095, p=6.22 x 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. ConclusionsOur 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.

genetics↗