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Mendelian randomiza...
Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases
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- Yuan, Shuai (författare)
- Karolinska Institutet
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- Wang, Lijuan (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.;Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland.
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- Zhang, Han (författare)
- Zhengzhou Univ, Coll Publ Hlth, Zhengzhou, Peoples R China.
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- Xu, Fengzhe (författare)
- Westlake Univ, Sch Life Sci, Key Lab Growth Regulat & Translat Res Zhejiang Pro, Hangzhou, Peoples R China.
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- Zhou, Xuan (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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- Yu, Lili (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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- Sun, Jing (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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- Chen, Jie (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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- Ying, Haochao (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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- Xu, Xiaolin (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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- Yu, Yongfu (författare)
- Fudan Univ, Sch Publ Hlth, Dept Biostat, Shanghai, Peoples R China.;Fudan Univ, Key Lab Publ Hlth Safety, Minist Educ, Shanghai, Peoples R China.
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- Spiliopoulou, Athina (författare)
- Univ Edinburgh, Usher Inst, Ctr Publ Hlth, Edinburgh, Scotland.
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- Shen, Xia (författare)
- Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland.;Fudan Univ, Greater Bay Area Inst Precis Med Guangzhou, Ctr Intelligent Med Res, Guangzhou, Peoples R China.;Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China.
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- Wilson, Jim (författare)
- Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland.
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- Gill, Dipender (författare)
- Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. Cambridge Inst Publ Hlth, Med Res Council, Biostat Unit, Cambridge, England. Univ Edinburgh, Med Res Council, Canc Res UK Edinburgh Ctr, Inst Genet & Canc, Edinburgh, Scotland. Uppsala Univ, Dept Surg Sci, Unit Med Epidemiol, Uppsala, Sweden.
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- Theodoratou, Evropi (författare)
- Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland.
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- Larsson, Susanna C. (författare)
- Karolinska Institutet,Uppsala universitet,Medicinsk epidemiologi,Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
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- Li, Xue (författare)
- Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
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Karolinska Institutet Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.;Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland. (creator_code:org_t)
- Elsevier, 2023
- 2023
- Engelska.
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 89
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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 autoim-mune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- Autoimmune disease
- Mendelian randomization
- Colocalization
- Drug development
- TYK2
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Yuan, Shuai
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Wang, Lijuan
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Zhang, Han
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Xu, Fengzhe
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Zhou, Xuan
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Yu, Lili
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visa fler...
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Sun, Jing
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Chen, Jie
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Ying, Haochao
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Xu, Xiaolin
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Yu, Yongfu
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Spiliopoulou, At ...
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Shen, Xia
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Wilson, Jim
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Gill, Dipender
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Theodoratou, Evr ...
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Larsson, Susanna ...
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Li, Xue
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Uppsala universitet
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