期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2115601119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Abdominal aortic aneurysm (AAA) is a common and severe disease with major genetic risk factors. In this study we generated enhancer-promoter contact data to identify regulatory elements in AAA-relevant cell types and identified changes in their predicted chromatin accessibility between AAA patients and controls. We integrated this information with disease-associated variants in regulatory elements and gene bodies to further understand the etiology and pathogenetic mechanisms of AAA. Our study combined whole-genome sequencing data with gene regulatory relations in disease-relevant cell types to reveal the important roles of the interleukin 6 pathway and
ERG and
KLF regulation in AAA pathogenesis.
Abdominal aortic aneurysm (AAA) is a common degenerative cardiovascular disease whose pathobiology is not clearly understood. The cellular heterogeneity and cell-type-specific gene regulation of vascular cells in human AAA have not been well-characterized. Here, we performed analysis of whole-genome sequencing data in AAA patients versus controls with the aim of detecting disease-associated variants that may affect gene regulation in human aortic smooth muscle cells (AoSMC) and human aortic endothelial cells (HAEC), two cell types of high relevance to AAA disease. To support this analysis, we generated H3K27ac HiChIP data for these cell types and inferred cell-type-specific gene regulatory networks. We observed that AAA-associated variants were most enriched in regulatory regions in AoSMC, compared with HAEC and CD4
+ cells. The cell-type-specific regulation defined by this HiChIP data supported the importance of
ERG and the
KLF family of transcription factors in AAA disease. The analysis of regulatory elements that contain noncoding variants and also are differentially open between AAA patients and controls revealed the significance of the interleukin-6-mediated signaling pathway. This finding was further validated by including information from the deleteriousness effect of nonsynonymous single-nucleotide variants in AAA patients and additional control data from the Medical Genome Reference Bank dataset. These results shed important insights into AAA pathogenesis and provide a model for cell-type-specific analysis of disease-associated variants.
