Abstract 1195: A Genomic Signature of Atherosclerosis among Individuals with Low Framingham Risk Score: The Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Background : The Framingham risk score (FRS) predicts low 10-year risks for the majority of women, even in the face of substantial burden of subclinical atherosclerosis (SA). However, many individuals predicted to be at low risk will still experience cardiovascular disease (CVD) events in the short term. We hypothesized that gene expression signatures in peripheral blood leukocytes (PBLs) could improve risk stratification among low-risk individuals, by identifying those with significant SA burden. Methods : We performed a case-control study of gene expression profiles among healthy women with low FRS (<10%) and no diabetes; we selected 49 cases with subclinical atherosclerosis (SA; defined as coronary artery calcification (CAC) >100 and carotid intima-media thickness (IMT) >1.0) and 72 age and race matched controls with CAC=0 and carotid IMT <0.65 from the MESA cohort. Microarray data were generated from Illumina BeadArray chips. Multiple cross-validation and gene ontology/pathway analysis were used to construct a classification model and identify genetic pathways involved in atherosclerosis. Results : A total of 2,462 genes with coefficient of variation >0.03 were used for data analysis. A gene signature composed of 40 to 60 genes in a support vector machine classification model was associated with an odds ratio of 3.5 for SA (p=0.002), resulting in a 71% specificity and 59% sensitivity for SA. For the 251 most differentially expressed genes (p = 10 −8 ~ 0.0004, false discovery rate (FDR) <0.2%) between those with and without SA, Ingenuity Pathway Analysis and Panther gene ontology analysis revealed this set of genes is enriched in innate immune function (p<10 −7 ). Notably, the majority of the top 30 genes (p<10 −6 , FDR<10 −6 ) were involved in toll-like receptor (TLR) signaling and hypoxia signaling. Conclusion : The results of functional genomic analysis suggest the activation of innate immune system through TLR signaling is associated with high burden of SA that can be detected in PBLs of healthy women predicted to be at low risk for CVD events. Our findings merit validation in a larger cohort.