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

IF 8.4 1区医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetologia Pub Date : 2024-09-13 DOI:10.1007/s00125-024-06267-5

Tea E. Heikkilä, Emilia K. Kaiser, Jake Lin, Dipender Gill, Jaakko J. Koskenniemi, Ville Karhunen

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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

Abstract Image

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以 IL-2、IL-6 和 TYK2 信号为靶点预防 1 型糖尿病疗效的遗传学证据：孟德尔随机研究

目的/假设我们旨在调查支持将已获许可或处于临床开发阶段的药物重新用于预防 1 型糖尿病的基因证据。方法我们获得了 1 型糖尿病风险、全血基因表达和血清蛋白水平的全基因组关联研究汇总统计，并调查了七个潜在药物靶基因附近的基因多态性。我们使用共定位法检测与 1 型糖尿病风险相关的基因变异是否也与相关的药物靶点基因代理相关，并使用孟德尔随机法评估关联的方向和程度。结果共同定位显示，IL2RA（编码IL-2受体亚基α [IL2RA]）、IL6R（编码IL-6受体[IL6R]）和IL6ST（编码IL-6细胞因子家族信号转导子[IL6ST]）的血液表达水平与相应基因附近的1型糖尿病责任具有相同的因果变异（后验概率分别为100%、96.5%和97.0%）。IL2RA、IL6R和IL6ST的基因代理基因表达量每增加1-SD，1型糖尿病的OR值（95% CI）分别为0.22（0.17，0.27）、1.98（1.48，2.65）和1.90（1.45，2.48）。结论/解释我们的研究结果支持以 IL-2、IL-6 和 TYK2 信号为靶点预防 1 型糖尿病。数据提供分析代码可在 https://github.com/jkoskenniemi/T1DSCREEN 上获取，其中还包括如何下载原始 GWAS 统计摘要的说明。图表摘要

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来源期刊

Diabetologia 医学-内分泌学与代谢

CiteScore

18.10

自引率

2.40%

发文量

193

审稿时长

1 months

期刊介绍： Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.