Cell Reports Medicine
Volume 3, Issue 11, 15 November 2022, 100805
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Article
Mendelian randomization and pathway analysis demonstrate shared genetic associations between lupus and coronary artery disease

https://doi.org/10.1016/j.xcrm.2022.100805Get rights and content
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Highlights

  • Genetic predisposition to SLE confers risk of CAD

  • Increased CVD risk in SLE involves atherosclerosis rather than cardiac dysfunction

  • PPI-based MR identifies pathways with causal implications between SLE and CAD

  • Pathway analysis informs therapeutic selection for managing CAD in SLE

Summary

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.

Keywords

systemic lupus erythematosus
coronary artery disease
Mendelian randomization
lupus
genetics
SNPs
targeted therapeutics
cardiovascular disease
genome-wide association study
pathway analysis

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