An Enhancer-Centric Approach Applied to Human Immune System Epigenomes Revealed the Association of Macrophage Enhancers with Cardiovascular Disease

Abstract Complex diseases are influenced by both genetic and environmental factors. Immune cells are key mediating interactions with the environment, but the impact of genetic variation on the immune system and how it influences complex diseases is not fully understood. Moreover, most genome-wide analyses (GWAS) variants associated with complex diseases are non-coding and difficult to interpret. Here, we investigated the association of non-coding variants with immune cell enhancers. As part of BLUEPRINT and the International Human Epigenome (IHEC) consortia, we generated and analysed a comprehensive set of epigenomes for human primary immune cells, including 107 epigenomes derived from 749 ChIP-Seq experiments across 24 cell types. We identified multicell enhancer activity patterns across the genome and examined their links with non-coding variants from 518 GWAS traits. This analysis revealed 117 significant associations, including novel links between cardiovascular disease variants and macrophage-specific enhancers that regulate genes involved in lipid metabolism and immunity, such as the gene encoding for the nuclear receptor LXR-alpha ( NR1H3) and many of its known target genes. Together, these data will help to better understand the influence of genetic variability in immune function and related diseases.