Gerard Pasterkamp (Netherlands)
University medical center Untrecht Central Diagnostics LaboratoryAuthor Of 3 Presentations
New Phenotypes for Stratification and Modeling of Atherosclerosis (ID 1320)
O008 - Proprotein Convertase Subtilisin/Kexin 6 is involved in lipid metabolism in liver and adipose tissue (ID 706)
Abstract
Background and Aims
PCSK6 is a protease strongly enriched in human liver however its function in liver has not been fully explored. Here, we aim to investigate the role of PCSK6 in lipid metabolism, and particularly in the context of atherosclerosis.
Methods
We used publically available datasets as well as biobanks to investigate the expression of PCSK6 in healthy and diseased tissues. In addition, we used Pcsk6-/- to investigate the effect of PCSK6 ablation.
Results
Genetic analyses of the PCSK6 locus identified a variant rs7181043 that was significantly associated with PCSK6 mRNA expression in healthy human adipose tissue, liver and in atherosclerotic plaques. The same variant was associated specifically with plaque fat content and atherosclerotic patient’s plasma LDL levels. In addition, PCSK6 mRNA expression in plaques was positively correlated with total plasma cholesterol and LDL levels in atherosclerotic patients. Further analyses using public scRNAseq data of healthy human livers, revealed that PCSK6 is expressed in hepatocytes and stellate cells. Microarray comparison of the livers from Pcsk6-/- mice and wild-type controls showed that VLDL particle assembly was one of the upregulated processes, in adipose tissue we found an increase in inflammatory infiltration and regulation of T cell mediated immunity. Preliminary in vivo studies showed that Pcsk6-/- mice have higher plasma cholesterol and LPL levels at baseline compared to controls, and lower levels of LDLR in their liver.
Conclusions
Our data suggests that PCSK6 is involved in cholesterol and metabolic control. Further experiments are warranted in order to understand the role of PCSK6 in lipid metabolism.
O013 - A multivariate analysis identifies genetic loci associated with atherosclerotic plaque composition and cardiovascular disease trajectory (ID 728)
Abstract
Background and Aims
From cross-sectional studies, we have learned that the composition of atherosclerotic plaques differs between individuals, and this contributes to the inter-individual differences in susceptibility to incident coronary and cerebral events. In pathological studies, the extent and type of atherosclerosis are commonly assessed based on histological plaque characteristics that are linked to plaque rupture and erosion. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. We investigated the genetics of the plaque through multivariate and integrative genome-wide analyses (GWAS) of individual plaque characteristics.
Methods
We included carotid endarterectomy patients from the Athero-Express Biobank Study (n = 2,124) with high-density imputed data and extensive histochemical plaque phenotyping available. We used slideToolKit to quantify the number of endothelial cells, macrophages and smooth muscle cells (SMCs), and manually assessed the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. We ran GWAS on all traits correcting for age, sex, array used, and genetic ancestry.
Results
We identified 3 loci that significantly associate with CD68+ macrophages and ACTA2+ SMCs, p < 5x10-8. Statistical fine-mapping revealed 9 variants in the 95% credible set and functional annotation linked these to genes associated with malignant neoplasms, circulating cholesterol, and transmembrane proteins, suggesting an effect on cellular proliferation and cholesterol metabolism.
Conclusions
We provide evidence for 3 loci that modulate plaque composition through macrophages and smooth muscle cell plaque proliferation and cell-cell interactions.