Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
Nat Genet. 2022 Jun;54(6):804-816. doi: 10.1038/s41588-022-01069-0. Epub 2022 May 19.
Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.
冠状动脉疾病 (CAD) 是一种涉及多种细胞类型遗传影响的复杂炎症性疾病。全基因组关联研究已经确定了 200 多个与 CAD 相关的位点，其中大多数风险变异位于影响顺式调控元件的非编码 DNA 序列中。在这里，我们应用了带有测序的转座酶可及染色质的单细胞分析，对来自 41 名不同 CAD 阶段患者的冠状动脉段的 28316 个核进行了分析，揭示了 14 个不同的细胞簇。我们在所有细胞中绘制了约 32 万个可及位点，鉴定了细胞类型特异性元件和转录因子，并对功能 CAD 风险变异进行了优先级排序。我们在平滑肌细胞转化状态中鉴定到了元件（例如成纤维肌细胞），并预测了功能性变体分别改变 MRAS（3q22）和 LIPA（10q23）的平滑肌细胞和巨噬细胞特异性调控。我们进一步提名了关键的驱动转录因子，如 PRDM16 和 TBX2。总之，这个单细胞图谱为解释 CAD 风险连续体中的调控机制提供了重要的一步。
