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. 2023 Mar:89:104488.
doi: 10.1016/j.ebiom.2023.104488. Epub 2023 Feb 24.

Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases

Shuai Yuan  1 , Lijuan Wang  2 , Han Zhang  3 , Fengzhe Xu  4 , Xuan Zhou  5 , Lili Yu  5 , Jing Sun  5 , Jie Chen  5 , Haochao Ying  5 , Xiaolin Xu  5 , Yongfu Yu  6 , Athina Spiliopoulou  7 , Xia Shen  8 , Jim Wilson  9 , Dipender Gill  10 , Evropi Theodoratou  11 , Susanna C Larsson  12 , Xue Li  13
Affiliations

Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases

Shuai Yuan et al. EBioMedicine. 2023 Mar.

Abstract

Background: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy.

Methods: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence.

Findings: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects.

Interpretation: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.

Funding: None.

Keywords: Autoimmune disease; Colocalization; Drug development; Mendelian randomization; TYK2.

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Conflict of interest statement

Declaration of interests DG is employed part-time by Novo Nordisk. The other authors declare no competing interest.

Figures

Fig. 1
Fig. 1
Study design overview.
Fig. 2
Fig. 2
Summary of results from Mendelian randomization (MR) analysis on disease outcomes. a, MR-PheWAS analysis of the associations between TYK2 loss-of-function mutation and health outcomes. b, MR analysis of the health effects of TYK2 inhibition on disease outcomes. c, Tissue-specific gene expression analysis for validating the associations between TYK2 expression and health outcomes. CI, confidence interval; OR, odds ratio; UKB, UK Biobank.
Fig. 3
Fig. 3
Biomarkers associated with additional minor (C) allele of rs34536443 in TYK2 gene regression. CI, confidence interval. The associations survived after multiple testing were labelled in the volcano plot.
See this image and copyright information in PMC

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