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. 2024 Dec;67(12):2667-2677.
doi: 10.1007/s00125-024-06267-5. Epub 2024 Sep 13.

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

Tea E Heikkilä  1 , Emilia K Kaiser  1 , Jake Lin  2   3 , Dipender Gill  4 , Jaakko J Koskenniemi  1   5 , Ville Karhunen  6   7   8
Affiliations

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

Tea E Heikkilä et al. Diabetologia. 2024 Dec.

Abstract

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.

Keywords: Co-localisation; IL-2; IL-6; Mendelian randomisation; TYK2; Type 1 diabetes.

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Conflict of interest statement

Acknowledgements: The authors wish to acknowledge CSC – IT Center for Science, Finland, for computational resources, the authors of original studies for summary statistics, T. Kinnunen (University of Eastern Finland) for helpful discussions, and two anonymous reviewers for insightful comments. During the preparation of this work the authors used ChatGPT version 4.0 to proofread and to improve the readability of the manuscript. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Data availability: Analysis code can be accessed at https://github.com/jkoskenniemi/T1DSCREEN , which also includes instructions on how to download the original GWAS summary statistics. Funding: This study was funded by Kyllikki ja Uolevi Lehikoisen säätiö, Foundation for Paediatric Research, Finnish Cultural Foundation, JDRF International (JJK); The University of Oulu & The Research Council of Finland Profi 326291 (VK); European Union’s Horizon 2020 research and innovation programme under grant agreement no. 848158 (EarlyCause) (VK); Wellcome Trust (225790/Z/22/Z) and the UK Research and Innovation Medical Research Council (MC_UU_00040/01) (VK). The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: JJK, VK and DG designed the study. JJK, VK and JL curated data. TEH and EKK analysed and visualised the data under supervision of JL, JJK and VK. TEH, EKK and JJK wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version to be published. All authors had access to data, and JJK, VK, JL, TEH and EKK accessed and verified the data. JJK, VK, TEH and EKK are guarantors for this article.

Figures

Fig. 1
Fig. 1
Regional Manhattan plot of whole-blood IL2RA expression (a) and risk of type 1 diabetes (b) near IL2RA (c). The colours indicate the LD r2 value with rs61839660 (the most likely shared causal variant identified in co-localisation), based on 1000Genomes European reference
Fig. 2
Fig. 2
Regional Manhattan plot of whole-blood IL6R expression (a) and risk of type 1 diabetes (b) near IL6R (c). The colours indicate the LD r2 value with rs10908839 (the most likely shared causal variant identified in co-localisation), based on 1000Genomes European reference
See this image and copyright information in PMC

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