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

Journal: EBioMedicine 2023;89():104488

PMID: 36842216

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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.

Address: 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.; 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.; College of Public Health, Zhengzhou University, Zhengzhou, China.; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.; School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Department of Biostatistics, School of Public Health, and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.; Centre for Public Health, Usher Institute, University of Edinburgh, Edinburgh, UK.; 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.; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.; 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.; 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: [email protected].; 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: [email protected].; School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].

DOI: 10.1016/j.ebiom.2023.104488

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MeSH Terms: Male, Humans, Mendelian Randomization Analysis, Genome-Wide Association Study, Autoimmune Diseases, Biomarkers, Psoriasis, Polymorphism, Single Nucleotide, TYK2 Kinase