Abstract 43: Increased Activation of Inflammatory Genes in Monocytes of Healthy People with Ischemic White Matter Disease

Abstract

Introduction: White matter hyperintensities (WMH) on MRI represent small vessel ischemic cerebrovascular disease. Greater WMH burden is associated with higher levels of circulating inflammatory cytokines in persons > 65 years with dementia, suggesting a pro-inflammatory vascular process. We hypothesized that middle-aged, asymptomatic, apparently healthy high risk people with high WMH burden would demonstrate increased inflammatory gene expression in monocytes analyzed with microarray. Methods: Subjects (N=70) were identified from a larger MRI study in 593 healthy family members of persons with early-onset CAD (< 60 years). We obtained monocytes and examined gene expression in all subjects (mean age 58.1 ± 10 years, range 30-73; 55% female; 36% African American). These included 35 subjects with the greatest WMH burden using volumetric methods in the larger study, and 35 unrelated age-sex-race matched controls with the lowest WMH burden. Monocyte mRNA was analyzed on Illumina Human HT12 v4 microarrays. We performed unsupervised principal component analysis (PCA) followed by ANOVA between high and low WMH groups. Genes with 2 SD differences in expression between groups were included for Gene Ontology permutation analysis using 1000 permutations within “GoMiner”. Only genes with the lowest false discovery rate (FDR) were summarized. Results: PCA identified no significant clustering. A total of 1,315 genes were included in gene ontology analysis and resulted in 10 ontological categories with an FDR<0.01%. This included 164 genes all showing greater expression in the high WMH group. These were key inflammatory genes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin-8 (IL-8), toll like receptor 5 and 7 (TLR5, TLR7) and integrin alpha 5 and M (ITGA5, ITGAM). Conclusions: Gene microarray ontological analysis of monocytes in healthy middle aged high risk people with greater WMH burden shows increased activation of genes of known innate inflammatory pathways. These findings likely reflect greater pro-inflammatory processes in persons with greater WMH, consistent with the presence of inflammation-mediated occult small vessel cerebrovascular disease in a healthy middle-aged population at increased risk for vascular diseases.