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

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Genetic evidence for efficacy of targeting IL-2, IL-6 and TYK2 signalling in the prevention of type 1 diabetes: a Mendelian randomisation study
Diabetologia ( IF 8.4 ) Pub Date : 2024-09-13 , DOI: 10.1007/s00125-024-06267-5
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}

Affiliation

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

中文翻译：

靶向 IL-2、IL-6 和 TYK2 信号传导预防 1 型糖尿病功效的遗传证据：孟德尔随机研究

目标/假设

我们的目的是调查支持重新利用已获得许可或处于临床开发阶段的药物来预防 1 型糖尿病的遗传证据。

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数据，并研究了 7 个潜在药物靶基因附近的遗传多态性。我们使用共定位来检查与 1 型糖尿病风险相关的相同遗传变异是否也与相关药物靶点遗传代理相关，并使用孟德尔随机化来评估关联的方向和程度。此外，我们进行了孟德尔随机化分析，仅限于药物靶基因内的功能变异。

结果

共定位显示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器 [IL6ST]）的血液表达水平与相应基因附近的 1 型糖尿病易感性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遗传代理基因表达每增加 1-SD，1 型糖尿病的 OR (95% CI) 分别为 0.22 (0.17, 0.27)、1.98 (1.48, 2.65) 和 1.90 (1.45, 2.48)。分别。使用错义变异，基因代理的TYK2 （编码酪氨酸激酶 2）表达水平与 1 型糖尿病风险相关（OR 0.61 [95% CI 0.54，0.69]）。