Publication Information: Uppsala universitet, Medicinsk epidemiologi
Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.;Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
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.
Zhengzhou Univ, Coll Publ Hlth, Zhengzhou, Peoples R China.
Westlake Univ, Sch Life Sci, Key Lab Growth Regulat & Translat Res Zhejiang Pro, Hangzhou, Peoples R China.
Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China.;Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Peoples R China.
Fudan Univ, Sch Publ Hlth, Dept Biostat, Shanghai, Peoples R China.;Fudan Univ, Key Lab Publ Hlth Safety, Minist Educ, Shanghai, Peoples R China.
Univ Edinburgh, Usher Inst, Ctr Publ Hlth, Edinburgh, Scotland.
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.
Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland.
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.
Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
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 autoim-mune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects. ; De två första författarna delar förstaförfattarskapet. De tre sista författarna delar sistaförfattarskapet.
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