AbstractPsoriasis is a chronic inflammatory skin disorder with multiple causes, including genetic and environmental factors. Despite advances in treatment, there remains a need to identify novel therapeutic targets. A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets for psoriasis.

摘要牛皮癣是一种慢性炎症性皮肤病，有多种原因，包括遗传和环境因素。尽管治疗取得了进展，但仍需要确定新的治疗靶点。进行孟德尔随机化（MR）分析以确定牛皮癣的治疗靶标。

Data on cis-expression quantitative trait loci were obtained from the eQTLGen Consortium (n = 31,684). Summary statistics for psoriasis (outcome) were sourced from the GWAS Catalog with a sample size of 484,598, including 5,427 cases and 479,171 controls. Colocalization analysis was used to assess whether psoriasis risk and gene expression were driven by shared single nucleotide polymorphisms.

顺式表达数量性状基因座的数据来自eQTLGen联盟（n=31684）。牛皮癣的汇总统计数据（结果）来自GWAS目录，样本量为484598，包括5427例病例和479171例对照。共定位分析用于评估牛皮癣风险和基因表达是否由共享的单核苷酸多态性驱动。

Drug prediction and molecular docking were utilized to validate the pharmacological value of the drug targets. The MR analysis found that 81 drug targets were significantly associated, and two (TYK2 and PRSS36) were supported by colocalization analysis (PP.H4 > 0.80). Phenome-wide association studies did not show any associations with other traits at the gene level.

利用药物预测和分子对接来验证药物靶标的药理学价值。MR分析发现，81个药物靶标显着相关，两个（TYK2和PRSS36）得到了共定位分析的支持（PP.H4 > 0.80）。全基因组关联研究未显示与基因水平上的其他性状有任何关联。

Biologically, these genes were closely related to immune function. Molecular docking revealed strong binding with drugs and proteins, as supported by available structural data. This study validated TYK2 as a drug target for psoriasis, in line with its existing clinical use, including the development of decucravacitinib.

生物学上，这些基因与免疫功能密切相关。分子对接揭示了与药物和蛋白质的强结合，这得到了可用结构数据的支持。这项研究验证了TYK2作为牛皮癣的药物靶标，符合其现有的临床应用，包括decucravacitinib的开发。

PRSS36 is a potential novel target requiring further investigation..

PRSS36是一个潜在的新目标，需要进一步研究。。

IntroductionPsoriasis is an inflammatory skin disease characterized by abnormal proliferation of keratin-forming cells and infiltration of the epidermis by immune cells, primarily affecting the skin, nails and joints, manifesting as plaque lesions on the skin1,2. Approximately 60 million people worldwide are affected by psoriasis, with prevalence rates varying geographically and being highest in Oceania, Western and Central Europe and North America3.

引言牛皮癣是一种炎症性皮肤病，其特征是角蛋白形成细胞异常增殖和免疫细胞浸润表皮，主要影响皮肤，指甲和关节，表现为皮肤上的斑块病变1,2。全世界约有6000万人受到牛皮癣的影响，患病率在地理上各不相同，大洋洲，西欧和中欧以及北美的患病率最高3。

The study by Dapeng Li4 indicated that the global age-standardized incidence rate of psoriasis showed a significant upward trend from 1990 to 2019, and the number of people affected is expected to increase further by 2040. Additionally, physical and psychological distress in patients, as well as substantial socioeconomic impacts, are caused by psoriasis.

李大鹏的研究表明，从1990年到2019年，全球银屑病的年龄标准化发病率呈显着上升趋势，预计到2040年，受影响的人数将进一步增加。此外，银屑病引起患者的身体和心理困扰以及重大的社会经济影响。

A study highlighted that the total economic burden of psoriasis in the USA was estimated to be $35.2 billion in 20135.Currently, psoriasis is a treatable but incurable disease. For mild to moderate psoriasis, a combination of topical treatments such as corticosteroids, vitamin D analogs and phototherapy can be used6.

一项研究强调，2013年美国牛皮癣的总经济负担估计为352亿美元。目前，牛皮癣是一种可治疗但无法治愈的疾病。。

Patients with moderate to severe psoriasis typically require systemic treatment. Although there have been advances in understanding the pathogenesis of psoriasis, a definitive cure for the disease remains elusive7. The current therapeutic challenges for psoriasis include drug delivery through psoriatic skin, which is often hardened, the physicochemical properties of some drugs, leading to poor absorption and efficacy8.

中度至重度牛皮癣患者通常需要全身治疗。尽管在了解牛皮癣的发病机制方面取得了进展，但该疾病的确切治愈方法仍然难以捉摸7。目前银屑病的治疗挑战包括通过银屑病皮肤递送药物，银屑病皮肤通常会变硬，一些药物的理化性质，导致吸收和疗效差8。

Therefore, the discovery of new protein targets for treating psoriasis is crucial.Randomized clinical trials are effective methods for assessing drug treatment strategies9. However, they require extensive planning, design and execution time, as w.

因此，发现用于治疗牛皮癣的新蛋白质靶标至关重要。随机临床试验是评估药物治疗策略的有效方法9。然而，它们需要大量的规划、设计和执行时间，因为w。

Data availability

数据可用性

The datasets analyzed during the current study are available in the in the following repositories: eQTLs data were obtained from eQTLGen Consortium (https://eqtlgen.org/); Psoriasis data was from a previous study and downloaded on GWAS Catalog (https://www.ebi.ac.uk/gwas/studies/GCST90038681).

当前研究期间分析的数据集可在以下存储库中获得：eQTLs数据来自eQTLGen Consortium(https://eqtlgen.org/)；牛皮癣数据来自先前的研究，并下载到GWAS目录中(https://www.ebi.ac.uk/gwas/studies/GCST90038681)。

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Download referencesAcknowledgementsWe thank the eQTLGen Consortium, the Dönertaş HM and other researchers and participants for providing publicly available data for this analysis.FundingNone.Author informationAuthor notesXin Guo and Mengjun Tao are the joint first authors of this work.Authors and AffiliationsSchool of Public Health, Wannan Medical College, No.

下载参考文献致谢我们感谢eQTLGen联盟，DönertaşHM和其他研究人员和参与者为这项分析提供了公开可用的数据。资金无。作者信息作者注释郭欣欣和陶梦君是这项工作的联合第一作者。作者和附属机构皖南医学院公共卫生学院，第号。

22, Wenchang West Road, Yijiang District, Wuhu, Anhui, ChinaXin Guo, XinCan Ji, MengQi Han, Yue Shen, Cheng Hong, HaoYang Guo, Wei Shi & Hui YuanDepartment of Health Management Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, ChinaMeng-jun TaoAuthorsXin GuoView author publicationsYou can also search for this author in.

中国安徽省芜湖市弋江区文昌西路22号郭新国，纪新灿，韩孟琦，岳深，程红，郭浩阳，魏世辉，皖南医学院附属第一医院卫生管理中心，中国芜湖市孟军陶作者郭新维作者出版物你也可以在中搜索这位作者。

PubMed Google ScholarMeng-jun TaoView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsXin Guo, Wei Shi and XinCan Ji conceptualized and designed the study. Xin Guo and XinCan Ji MengQi Han, Yue Shen and Cheng Hong collected data and were involved in analysis and visualization. Xin Guo wrote the original draft. Mengjun Tao was responsible for editing the draft.

PubMed谷歌学术贡献Xin Guo，Wei Shi和XinCan Ji概念化并设计了这项研究。Xin Guo和XinCan Ji MengQi Han，Yue Shen和Cheng Hong收集数据并参与分析和可视化。郭欣写了原稿。孟俊涛负责编辑草案。

Hui Yuan was responsible for review, editing the draft and funding acquisition. Xin Guo and Mengjun Tao contributed equally to this work. All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

慧远负责审查、编辑草案和资金获取。Xin Guo和Mongjun Tao对这项工作做出了同样的贡献。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Wei Shi or Hui Yuan.Ethics declarations

魏氏或慧元。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval and consent to participate

道德批准和同意参与

Not applicable because it was a secondary data analysis.

不适用，因为这是二次数据分析。

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Reprints and permissionsAbout this articleCite this articleGuo, X., Tao, Mj., Ji, X. et al. Validation of TYK2 and exploration of PRSS36 as drug targets for psoriasis using Mendelian randomization.

转载和许可本文引用本文Guo，X.，Tao，Mj。，Ji，X。等人。使用孟德尔随机化验证TYK2和探索PRSS36作为牛皮癣的药物靶标。

Sci Rep 14, 23902 (2024). https://doi.org/10.1038/s41598-024-74148-3Download citationReceived: 12 March 2024Accepted: 24 September 2024Published: 13 October 2024DOI: https://doi.org/10.1038/s41598-024-74148-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1423902（2024）。https://doi.org/10.1038/s41598-024-74148-3Download引文接收日期：2024年3月12日接受日期：2024年9月24日发布日期：2024年10月13日OI：https://doi.org/10.1038/s41598-024-74148-3Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsPsoriasisMendelian randomizationDrug targetsGenetics

关键词SPSORISSMENDELIAN随机化药物靶标遗传学