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; Emilia K. Kaiser; Jake Lin; Dipender Gill; Jaakko J. Koskenniemi; Ville Karhunen

doi:10.1007/s00125-024-06267-5

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
, Emilia K. Kaiser
, Jake Lin
, Dipender Gill
, Jaakko J. Koskenniemi
, Ville Karhunen^*

^*Corresponding author for this work

Health Sciences

Research output: Contribution to journal › Article › Scientific › peer-review

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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. Graphical Abstract: (Figure presented.)

Original language	English
Pages (from-to)	2667-2677
Number of pages	11
Journal	Diabetologia
Volume	67
Early online date	2024
DOIs	https://doi.org/10.1007/s00125-024-06267-5
Publication status	Published - 2024
Publication type	A1 Journal article-refereed

Funding

This study was funded by Kyllikki ja Uolevi Lehikoisen s\u00E4\u00E4ti\u00F6, Foundation for Paediatric Research, Finnish Cultural Foundation, JDRF International (JJK); The University of Oulu & The Research Council of Finland Profi 326291 (VK); European Union\u2019s 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.

Funders	Funder number
Suomen Kulttuurirahasto
Kyllikki ja Uolevi Lehikoisen säätiö, Foundation for Paediatric Research
Juvenile Diabetes Research Foundation United States of America
University of Oulu & The Research Council of Finland	326291
Horizon 2020 Framework Programme	848158
Horizon 2020 Framework Programme
Wellcome Trust	225790/Z/22/Z
Wellcome Trust
UK Research and Innovation Medical Research Council	MC_UU_00040/01

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Co-localisation
IL-2
IL-6
Mendelian randomisation
TYK2
Type 1 diabetes

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

Access to Document

10.1007/s00125-024-06267-5Licence: CC BY

s00125-024-06267-5Final published version, 1.6 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202411069966Licence: CC BY

Cite this

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

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. Graphical Abstract: (Figure presented.)",

keywords = "Co-localisation, IL-2, IL-6, Mendelian randomisation, TYK2, Type 1 diabetes",

author = "Heikkil{\"a}, \{Tea E.\} and Kaiser, \{Emilia K.\} and Jake Lin and Dipender Gill and Koskenniemi, \{Jaakko J.\} and Ville Karhunen",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1007/s00125-024-06267-5",

language = "English",

volume = "67",

pages = "2667--2677",

journal = "Diabetologia",

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TY - JOUR

T1 - Genetic evidence for efficacy of targeting IL-2, IL-6 and TYK2 signalling in the prevention of type 1 diabetes

T2 - a Mendelian randomisation study

AU - Heikkilä, Tea E.

AU - Kaiser, Emilia K.

AU - Lin, Jake

AU - Gill, Dipender

AU - Koskenniemi, Jaakko J.

AU - Karhunen, Ville

PY - 2024

Y1 - 2024

N2 - 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: (Figure presented.)

AB - 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: (Figure presented.)

KW - Co-localisation

KW - IL-2

KW - IL-6

KW - Mendelian randomisation

KW - TYK2

KW - Type 1 diabetes

U2 - 10.1007/s00125-024-06267-5

DO - 10.1007/s00125-024-06267-5

M3 - Article

AN - SCOPUS:85204149003

SN - 0012-186X

VL - 67

SP - 2667

EP - 2677

JO - Diabetologia

JF - Diabetologia

ER -

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

Abstract

Funding

UN SDGs

Keywords

Publication forum classification

ASJC Scopus subject areas

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Cite this