Abstract 10863: Genome-Wide Assessments of 138 Inflammatory Markers Identified Inflammatory Pathways Confer Cardiovascular Disease Risk

Introduction: Atherosclerosis, the main underlying causes of coronary heart disease (CHD) and ischemic stroke, is an inflammatory condition. However, therapeutics targeting inflammation for CHD and stroke are limited, partially due to insufficient evidence for causal inflammatory pathways and druggable targets. Objectives: We aimed to identify causal inflammatory markers for CHD and ischemic stroke, and to characterize the genetic architecture shared between such an inflammatory profile and CHD/stroke. Methods: Pooling multiple databases, we curated the largest genome-wide association summary statistics for 138 markers including 126 inflammatory proteins (C-reactive protein [CRP], N>450k; others such as cytokines, N~3.6k-45k) and 12 blood immune cell types (N>450k) and subsets (N~2.5k); as well as for CHD (N~547k) and stroke (N~521k). We conducted Mendelian randomization (MR) analysis using Causal Analysis Using Summary Effect Estimates and Mode-Based Estimate; and the genome-wide cross-trait meta-analysis using Association analysis based on SubSETs. Results: Of the 138 inflammatory markers, MR analyses identified 3 cellular and 4 protein markers showing significant causal effects for CHD (including white blood cell count, CD8+ T count, interleukin 6, and interleukin 22 receptor subunit alpha 1; FDR <0.05); and 4 protein markers showing significant causal effects for ischemic stroke (including interleukin 6 and macrophage migration inhibitory factor; FDR <0.05). Genome-wide cross-trait analysis identified 456 independent genetic loci that significantly co-regulated cardiovascular disease (CHD or stroke) and at least one of its causal inflammatory markers (e.g., APOC1-4 coregulated CHD and 5 causal markers for CHD; lead SNPs showing P <5e-8 in each pair of marker-disease meta-analysis and FDR <0.01 with each trait). In tissue-specific gene expression analysis, the expressions of genes harboring these loci showed a significant enrichment in blood, blood vessels, and adipose tissue ( FDR <0.05), and a marginal enrichment in the liver and lung ( P <0.05). Conclusions: We identified cellular and protein inflammatory markers that potentially have a causal role in the development of CHD and ischemic stroke, based on genetic evidence.