Genetic architecture of cytokine autoantibodies and associated risk of common diseases

Abstract

Anti-cytokine autoantibodies are increasingly recognized as modulators of immune function and determinants of disease risk, yet their genetic basis and population-level impact remain unclear. Here we perform genome-wide association studies of autoantibodies against IL-1α, IL-6, IL-10, IFN-α, IFN-β, IFN-γ and GM-CSF in 15,000 individuals from the Danish Blood Donor Study. We identify 52 genome-wide significant loci, implicating genes enriched in antigen-presentation pathways. Using these data, we derive cytokine-specific polygenic risk scores and evaluate their associations across 300,000 individuals in the Copenhagen Hospital Biobank. Genetic predisposition to IL-1α autoantibodies is associated with reduced risk of rheumatoid arthritis and certain cancers, whereas genetic predisposition to IL-6 autoantibodies is associated with increased risk of diabetes, mirroring prior clinical observations. These findings define the genetic architecture of anti-cytokine autoantibodies and indicate their divergent effects on human disease risk at population scale, providing a framework for mechanistic investigation and potential clinical stratification. Despite limited understanding of cytokine autoantibodies, this study reveals a heterogeneous genetic architecture, with distinct profiles conferring reduced risk of certain cancers and rheumatoid arthritis, but increased susceptibility to diabetes.