Inflammatory pathways as drug targets for autoimmune disease

Konieczny, Marek (2025): Inflammatory pathways as drug targets for autoimmune disease: insights from human genomics. Dissertation, LMU München: Medizinische Fakultät

Abstract

Inflammation contributes to the pathophysiology underlying multiple human diseases, including allergic and autoimmune disease, cardiometabolic disease and cancer. Circulating cytokines are central in orchestrating inflammation and immune responses and are increasingly recognized as promising targets for therapeutic interventions. Indeed, cytokine-based immunotherapies are already approved and part of the therapeutic armamentarium for autoimmune diseases and cancer. Nevertheless, repurposing of cytokine-based compounds to other conditions, for example to cardiovascular disease, remains limited due to efficacy and safety issues. Development and validation of drug targets with the help of human genomics received much attention in recent years with increased data availability and low costs showing enormous potential. Researchers quantifying the added value of genomics for drug development have shown that compounds backed-up by in-silico data are more than twice as likely to receive marketing approval compared to targets without genetic support. During my MD project, I conducted the largest genomewide association study (GWAS) to date on a panel of 40 circulating cytokines, encompassing 74.783 individuals, followed by extensive post-GWAS analyses including transcriptome-wide association studies followed by Mendelian randomization (TWAS-MR), drug-target MR and colocalization to study the genetic architecture of circulating cytokines and uncover novel drug targets for human diseases. In my analysis, I identified a total of 359 significant associations between circulating cytokine levels and genetic variants, spanning 169 distinct genomic loci. By integrating the GWAS findings with transcriptomic data, I uncovered crucial regulatory mechanisms underlying cytokine expression. For instance, the analysis revealed a significant role of ACKR1 in buffering multiple chemokines, acting as a scavenger to regulate their levels effectively. Additionally, I identified TRAFD1 as a key modulator of the cytokine storm induced by TNF signaling. Cross-cytokine MR analysis unveiled a complex network of interconnections among cytokines, with TNF-b, VEGF, and IL-1ra emerging as central players with pleiotropic downstream effects on multiple other cytokines. Employing drug-target MR in conjunction with colocalization analysis, I uncovered potential causal mediators underlying specific diseases. Notably, my analysis identified G-CSF and CXCL9/MIG as potential drivers of asthma and Crohn’s disease, respectively. Additionally, I observed a potentially protective role of TNF-b in multiple sclerosis. My findings offer a comprehensive insight into the genetic landscape governing circulating cytokines, paving the way for targeted immunotherapy development.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: cytokines, autoimmune disease, genomics, drug targets
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 7. Mai 2025
• 1. Bericht­erstatter:in: Georgakis, Marios