Genome wide associations with silent atherosclerosis

Background Atherosclerotic cardiovascular disease is a leading cause of death globally. Atherosclerosis is a progressive and systemic condition with a prolonged silent phase before causing irreversible end-organ damage through conditions such as ischemic heart disease, stroke, and peripheral artery disease. Despite the systemic nature of the disease, the majority of all genetic evaluations have focused on specific clinical events, such as myocardial infarction. Purpose The aim of this study is to investigate the genetic basis for silent atherosclerosis in a genome-wide association study. Methods We included Danish citizens aged 18 to 70 years old and with no history of atherosclerotic cardiovascular disease from the REACT study. We used 3D vascular ultrasound (3DVUS) to measure the volume of atherosclerotic plaque in the carotid and femoral arteries bilaterally and combined this with CT-angiography of the coronary arteries into a comprehensive assessment of silent atherosclerosis. We genotyped participants using the Illumina Global Screening Array and imputed common variants using the 1000 genomes phase 3 reference panel. We performed GWAS with plink2 including age, sex, and the first 10 principal components as covariates to identify germline variants associated with two outcomes: (1) absence/presence of plaque in any vascular territory scanned with a logistic regression and (2) 3DVUS plaque burden in the log-scale for individuals with a significant plaque according to Mannheim criteria with a linear regression. Results 3,271 individuals (median age 54 years (IQR 46-61), 51% female) were assessed to identify variants associated with plaque presence. From them, 1,084 individuals (33%) with significant plaque were included in the analysis to identify variants associated with 3DVUS plaque burden. A potential novel SNP near SLC22A3 gene was found to be enriched in participants with at least one plaque, although this finding didn’t reach statistical significance after multiple adjustment. QQ plots and Manhattan plots are shown in Figure 1. Summary statistics for this novel hit as well as known hits from different phenotypes are shown in table 1. We saw a nominally significant association with a variant in the APOE gene, which is a well-established hit for LDL-cholesterol, but no association with 9p21 locus, which has previously been associated with coronary artery disease. We also saw a nominally significant association with the variant in EDNRA, which has previously been reported to be association with carotid atherosclerosis Conclusion A potential novel hit for silent atherosclerosis has been found in this preliminary analysis from the REACT study. Further research is needed to validate this finding.Figure 1Table 1