Genetic evidence for efficacy of targeting IL-2, IL-6 and TYK2 signalling in the prevention of type 1 diabetes: a Mendelian randomisation study

• Published in: Diabetologia 2024-12, Vol.67 (12), p.2667-2677
• Main Authors: Heikkilä, Tea E., Kaiser, Emilia K., Lin, Jake, Gill, Dipender, Koskenniemi, Jaakko J., Karhunen, Ville
• Format: Article
• Language: English
• Subjects: Blood levels; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Disease prevention; Drug development; Gene expression; Gene polymorphism; Genetic analysis; Genetic diversity; Genetic Predisposition to Disease; Genetics; Genome-wide association studies; Genome-Wide Association Study; Human Physiology; Humans; Interleukin 2; Interleukin 2 receptors; Interleukin 6; Interleukin 6 receptors; Interleukin-2 - genetics; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Internal Medicine; Kinases; Localization; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mendelian Randomization Analysis; Metabolic Diseases; Polymorphism, Single Nucleotide; Receptors, Interleukin-6 - genetics; Signal Transduction - genetics; Statistical analysis; Therapeutic targets; TYK2 Kinase - genetics; TYK2 Kinase - metabolism; Tyk2 protein
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-024-06267-5

Aims/hypothesis We aimed to investigate the genetic evidence that supports the repurposing of drugs already licensed or in clinical phases of development for prevention of type 1 diabetes. Methods We obtained genome-wide association study summary statistics for the risk of type 1 diabetes, whole-blood gene expression and serum protein levels and investigated genetic polymorphisms near seven potential drug target genes. We used co-localisation to examine whether the same genetic variants that are associated with type 1 diabetes risk were also associated with the relevant drug target genetic proxies and used Mendelian randomisation to evaluate the direction and magnitude of the associations. Furthermore, we performed Mendelian randomisation analysis restricted to functional variants within the drug target genes. Results Co-localisation revealed that the blood expression levels of IL2RA (encoding IL-2 receptor subunit α [IL2RA]), IL6R (encoding IL-6 receptor [IL6R]) and IL6ST (encoding IL-6 cytokine family signal transducer [IL6ST]) shared the same causal variant with type 1 diabetes liability near the corresponding genes (posterior probabilities 100%, 96.5% and 97.0%, respectively). The OR (95% CI) of type 1 diabetes per 1-SD increase in the genetically proxied gene expression of IL2RA , IL6R and IL6ST were 0.22 (0.17, 0.27), 1.98 (1.48, 2.65) and 1.90 (1.45, 2.48), respectively. Using missense variants, genetically proxied TYK2 (encoding tyrosine kinase 2) expression levels were associated with type 1 diabetes risk (OR 0.61 [95% CI 0.54, 0.69]). Conclusions/interpretation Our findings support the targeting of IL-2, IL-6 and TYK2 signalling in prevention of type 1 diabetes. Data availability The analysis code is available at https://github.com/jkoskenniemi/T1DSCREEN , which also includes instructions on how to download the original GWAS summary statistics. Graphical Abstract