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Mendelian randomization and pathway analysis demonstrate shared genetic associations between lupus and coronary

Jessica Kain1, Katherine A Owen1, Miranda C Marion2

  • 1AMPEL BioSolutions, LLC, Charlottesville, VA, USA; The RILITE Research Institute, Charlottesville, VA, USA.

Cell Reports. Medicine
|November 5, 2022
PubMed

Insights

Systemic lupus erythematosus (SLE) significantly increases the risk of coronary artery disease (CAD). This study used genetic analysis to identify causal pathways, revealing therapeutic targets for managing CAD in SLE patients.

Area of Science:

  • Genetics
  • Immunology
  • Cardiology

Background:

  • Coronary artery disease (CAD) is a primary cause of mortality in patients with systemic lupus erythematosus (SLE).
  • Existing genetic studies on the association between SLE and CAD are limited, focusing on a few common risk loci.
  • There is a need for comprehensive genetic analyses to understand the pleiotropic effects influencing both conditions.

Purpose of the Study:

  • To investigate the causal genetic links between SLE and CAD using advanced Mendelian randomization (MR) techniques.
  • To identify specific biological pathways and networks implicated in the co-occurrence of SLE and CAD.
  • To uncover potential therapeutic targets for mitigating CAD risk in SLE patients.

Main Methods:

  • Employed traditional Mendelian randomization (MR) to estimate the causal effect of SLE-associated SNPs on CAD.
  • Utilized SNP-to-gene mapping and protein-protein interaction (PPI) network analysis for pathway identification.
  • Applied a PPI-based MR approach using functional gene sets as instrumental variables to confirm causal effects.

Main Results:

  • Identified a net positive causal estimate of SLE-associated non-HLA SNPs on CAD.
  • Discovered distinct biological networks with both positive and negative causal gene sets connecting SLE and CAD.
  • Confirmed the causal influence of specific SNP-to-gene modules on CAD risk.

Conclusions:

  • The study elucidates molecular pathways causally linking SLE and CAD.
  • Identified biological pathways likely contributing to both diseases, offering insights into shared pathogenesis.
  • Revealed potential novel and existing therapeutic strategies for managing CAD in the context of SLE.

Keywords:
Mendelian randomizationSNPscardiovascular diseasecoronary artery diseasegeneticsgenome-wide association studylupuspathway analysissystemic lupus erythematosustargeted therapeutics

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