Genetically determined ancestry associates with morphological and molecular carotid plaque features

Atherosclerosis, the main driver of cardiovascular disease (CVD), is influenced by a plethora of risk factors, including age, gender, and diabetes, that correlate with socio-economic status and may vary across ethnicities. These factors fail to fully explain observed ethnic disparities in CVD burden. For example, coronary artery calcification increases with age regardless of ethnicity, yet CAC is more prevalent in individuals of European descent. As these findings may be confounded by self-reported ethnicity, genome-informed ancestry offers a more accurate lens through which to study these ancestral differences. Yet, the biological basis of atherosclerotic plaque development and composition across ancestries remains essential underexplored. We hypothesized that genetically determined ancestry is associated with morphological and molecular features of atherosclerotic plaques. Leveraging the Athero-Express Biobank Study, an ongoing Dutch cohort with deep histological and transcriptomic profiling of plaques, we analyzed data from 1944 patients after genotype quality control and ancestry inference using principal component analysis against 1000 Genomes. Two ancestry groups were identified, European (n = 1866) and non-European (n = 51), reflecting Netherlands' migratory history. Demographics were largely comparable between groups, however, ordinal logistic regression showed non-European ancestries had higher odds of increase plaque vulnerability (OR = 1.67, 95% CI 1.01-2.77, p = 0.0450), a finding that remained robust after down sampling. Differential gene expression analysis highlighted NLGN4X and CADM3 among the top differentially expressed genes, representing biologically relevant pathways related to synaptic and cell-cell adhesion. Pathway and single-cell enrichment analyses, including through integration with genome-wide association study data, further revealed consistent enrichment of inflammation-related biological processes and diseases. Our findings support that genetic ancestry correlates with morphological and molecular plaque composition, with non-European patients showing more inflammatory, higher-risk plaque features, including inflammatory signatures. Increased ancestral diversity in vascular biology research is critical for understanding atherosclerotic pathophysiology and develop equitable and personalized therapeutic strategies.