Kain Jessica, Owen Katherine A, Marion Miranda C, Langefeld Carl D, Grammer Amrie C, Lipsky Peter E
AMPEL BioSolutions, LLC, Charlottesville, VA, USA; The RILITE Research Institute, Charlottesville, VA, USA.
AMPEL BioSolutions, LLC, Charlottesville, VA, USA; The RILITE Research Institute, Charlottesville, VA, USA.
Cell Rep Med. 2022 Nov 15;3(11):100805. doi: 10.1016/j.xcrm.2022.100805. Epub 2022 Nov 4.
Coronary artery disease (CAD) is a leading cause of death in patients with systemic lupus erythematosus (SLE). Despite clinical evidence supporting an association between SLE and CAD, pleiotropy-adjusted genetic association studies are limited and focus on only a few common risk loci. Here, we identify a net positive causal estimate of SLE-associated non-HLA SNPs on CAD by traditional Mendelian randomization (MR) approaches. Pathway analysis using SNP-to-gene mapping followed by unsupervised clustering based on protein-protein interactions (PPIs) identifies biological networks composed of positive and negative causal sets of genes. In addition, we confirm the casual effects of specific SNP-to-gene modules on CAD using only SNP mapping to each PPI-defined functional gene set as instrumental variables. This PPI-based MR approach elucidates various molecular pathways with causal implications between SLE and CAD and identifies biological pathways likely causative of both pathologies, revealing known and novel therapeutic interventions for managing CAD in SLE.
冠状动脉疾病（CAD）是系统性红斑狼疮（SLE）患者的主要死因。尽管有临床证据支持SLE与CAD之间存在关联，但多效性调整后的基因关联研究有限，且仅关注少数常见风险位点。在此，我们通过传统的孟德尔随机化（MR）方法确定了SLE相关非HLA单核苷酸多态性（SNP）对CAD的净正向因果估计。使用SNP到基因的映射进行通路分析，随后基于蛋白质-蛋白质相互作用（PPI）进行无监督聚类，识别出由正负因果基因集组成的生物网络。此外，我们仅使用映射到每个PPI定义的功能基因集的SNP作为工具变量，确认了特定SNP到基因模块对CAD的因果效应。这种基于PPI的MR方法阐明了SLE和CAD之间具有因果关系的各种分子途径，并识别出可能导致两种疾病的生物途径，揭示了治疗SLE中CAD的已知和新型治疗干预措施。
