| Title: | Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases |
| Journal: | EBioMedicine |
| Published: | 24 Feb 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36842216/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2023.104488 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988426 |
Publication 11129
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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.</p>
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.</p>
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.</p>
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.</p>
FUNDING: None.</p>
18 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
1 Application
| Application ID | Title |
|---|---|
| 66354 | Investigating the genetic, environmental and clinical determinants and their interactions on cancer risk, and developing risk prediction and prognosis models for common cancer types |
Enabling scientific discoveries that improve human health