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

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

doi:10.1016/j.ebiom.2023.104488

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

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

Authors

Shuai Yuan¹, Lijuan Wang², Han Zhang³, Fengzhe Xu⁴, Xuan Zhou⁵, Lili Yu⁵, Jing Sun⁵, Jie Chen⁵, Haochao Ying⁵, Xiaolin Xu⁵, Yongfu Yu⁶, Athina Spiliopoulou⁷, Xia Shen⁸, Jim Wilson⁹, Dipender Gill¹⁰, Evropi Theodoratou¹¹, Susanna C Larsson¹², Xue Li¹³

Affiliations

¹ School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
² School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
³ College of Public Health, Zhengzhou University, Zhengzhou, China.
⁴ Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
⁵ School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Department of Biostatistics, School of Public Health, and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
⁷ Centre for Public Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁸ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK; Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁹ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
¹¹ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. Electronic address: e.theodoratou@ed.ac.uk.
¹² Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Electronic address: susanna.larsson@ki.se.
¹³ School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: xueli157@zju.edu.cn.

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.

Publication types

Systematic Review

MeSH terms

Autoimmune Diseases*
Biomarkers
Genome-Wide Association Study
Humans
Male
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Psoriasis* / etiology
TYK2 Kinase / genetics

Substances

Biomarkers
TYK2 protein, human
TYK2 Kinase

Grants and funding

22804/CRUK_/Cancer Research UK/United Kingdom