Lipid-Induced Epigenomic Changes in Human Macrophages Identify a Coronary Artery Disease-Associated Variant that Regulates Expression through Altered C/EBP-Beta Binding

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Coronary artery disease is a complex disease where over 40 genomic loci contributing to genetic risk have been identified. However, identifying the precise variants, genomic elements and genes that mediate this risk at each locus has proved challenging. We hypothesized that some genetic risk variants may influence a key step in development of coronary artery disease, which occurs when macrophages encounter environmentally-derived lipid. These cells take up lipid and accumulate in atherosclerotic plaques in the walls of blood vessels where they contribute to the inflammatory atherosclerotic disease process. Therefore, we studied the effects of this lipid exposure on the genomic activity of these cells. Environmental lipid exposure triggered changes in transcriptional regulation and gene expression. Variants at coronary artery disease risk loci were enriched for genomic regions altered by lipid exposure. We studied one such risk variant rs72664324 in detail and found that it altered binding of the C/EBP-beta transcription factor and altered expression of the PPAP2B gene. PPAP2B encodes an enzyme that degrades pro-inflammatory substances. Our study demonstrates a hitherto unknown genetic mechanism underlying atherosclerotic heart disease and demonstrates the value of studying changes in transcriptional regulation in key disease processes involving environmental influences.

Vyšlo v časopise: Lipid-Induced Epigenomic Changes in Human Macrophages Identify a Coronary Artery Disease-Associated Variant that Regulates Expression through Altered C/EBP-Beta Binding. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005061
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005061

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