Mendelian Randomization and Clinical Trial Evidence Supports TYK2 Inhibition As a Therapeutic Target for Autoimmune Diseases

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2023 Feb 26

PMID 36842216

Authors

Shuai Yuan

Lijuan Wang

Han Zhang

Fengzhe Xu

Xuan Zhou

Lili Yu

Jing Sun

Jie Chen

Haochao Ying

Xiaolin Xu

Yongfu Yu

Athina Spiliopoulou

Xia Shen

Jim Wilson

Dipender Gill

Evropi Theodoratou

Susanna C Larsson

Xue Li

Affiliations

Soon will be listed here.

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.

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