Genetic Commonalities Between Metabolic Syndrome and Rheumatic Diseases Through Disease Interactome Modules

ABSTRACT This study aims to elucidate the potential genetic commonalities between metabolic syndrome (MetS) and rheumatic diseases through a disease interactome network, according to publicly available large‐scale genome‐wide association studies (GWAS). The analysis included linkage disequilibrium score regression analysis, cross trait meta‐analysis and colocalisation analysis to identify common genetic overlap. Using modular partitioning, the network‐based association between the two disease proteins in the protein–protein interaction set was divided and quantified. Clinical samples from public databases were used to confirm the mapped genes. Mendelian randomisation analyses were conducted using genetic instrumental variables for causal inference. MetS and rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and their primary module networks shared topological overlap and genetic correlation. Functional analysis highlighted the significance of these shared targets in processes such as a diverse array of metabolic pathways involving glucose, lipids, energy, protein transport, inflammatory response, autophagy and cytokine regulation, elucidating the pathways through which MetS intersects with rheumatic diseases. Causal associations were determined between MetS phenotypes and rheumatic diseases. The persistence of MetS effects on rheumatic diseases remained evident even after adjusting for alcohol consumption and smoking. We have highlighted specific genetic associations between MetS and rheumatic diseases. Several genes (e.g., PRRC2A, PSMB8, BAG6, GPSM3, PBX2, etc.) have been identified with molecular commonalities in MetS and RA, AS, SLE and SS, which may serve as potential targets for shared treatments.