AbstractThis study explored the causal relationships among primary sclerosing cholangitis (PSC), ulcerative colitis (UC), and hepatobiliary cancer (HBC) by using bidirectional two-sample, two-step Mendelian randomization (MR) analysis. Genetic variants associated with PSC and UC from the FinnGen research database were used for instrumental variable-based analyses.

摘要本研究通过双向双样本两步孟德尔随机（MR）分析探讨了原发性硬化性胆管炎（PSC），溃疡性结肠炎（UC）和肝胆癌（HBC）之间的因果关系。FinnGen research数据库中与PSC和UC相关的遗传变异用于基于工具变量的分析。

Mediation analyses were conducted to examine the role of PSC and UC in HBC risk. The findings revealed a causal effect of genetic predisposition to UC on PSC risk (inverse-variance-weighted [IVW] analysis odds ratio [OR] 1.145, p < 0.001), whereas no reverse causality was observed. Although UC showed no direct causal effect on HBC risk, genetic susceptibility to PSC significantly increased the risk of HBC (IVW analysis OR = 1.855, p < 0.001).

进行调解分析以检查PSC和UC在HBC风险中的作用。这些发现揭示了UC遗传易感性对PSC风险的因果关系（逆方差加权[IVW]分析优势比[OR]1.145，p < 0.001), 而没有观察到反向因果关系。尽管UC对HBC风险没有直接的因果关系，但对PSC的遗传易感性显着增加了HBC的风险（IVW分析或 = 1.855, p<0.001）。

Mediation analysis further identified PSC as a significant mediator amplifying the causal effect of UC on HBC risk (effect size = 0.083). These results established a causal link between genetic susceptibility to UC and increased risk of PSC, and highlighted the critical role of PSC in mediating the impact of UC on HBC risk..

调解分析进一步确定PSC是放大UC对HBC风险的因果关系的重要中介（效应大小 = 0.083). 这些结果建立了UC遗传易感性与PSC风险增加之间的因果关系，并强调了PSC在介导UC对HBC风险的影响中的关键作用。。

IntroductionHepatobiliary cancer (HBC) includes primary liver cancers, such as hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and gallbladder cancer (GBC). HBC is the sixth most common malignancy and the third leading cause of cancer-related mortality. Given the marked increase in susceptibility to HCC as compared to the general population, primary sclerosing cholangitis (PSC) has garnered attention as a potential predisposing factor for hepatobiliary cancer1.

简介肝胆癌（HBC）包括原发性肝癌，如肝细胞癌（HCC），胆管癌（CC）和胆囊癌（GBC）。HBC是第六大最常见的恶性肿瘤，也是癌症相关死亡率的第三大原因。鉴于与普通人群相比，对HCC的易感性显着增加，原发性硬化性胆管炎（PSC）作为肝胆癌的潜在易感因素引起了人们的关注1。

PSC is a rare, chronic, immune-mediated cholangiopathy characterized by inflammation and progressive fibrotic narrowing of the bile ducts2,3. Existing literature demonstrates a recent increase in its prevalence, with reported rates ranging from 0.78 to 31.7 per 100,000 individuals4. Although the prevailing consensus attributes PSC to a combination of environmental and genetic factors, the precise etiology of this condition remains elusive3.

PSC是一种罕见的慢性免疫介导的胆管疾病，其特征是炎症和胆管进行性纤维化狭窄2,3。现有文献表明，其患病率最近有所增加，报告率从每10万人0.78到31.7不等4。尽管普遍的共识将PSC归因于环境和遗传因素的结合，但这种情况的确切病因仍然难以捉摸3。

The natural progression of PSC culminates in the emergence of biliary cirrhosis and eventually in liver failure, with the potential for further advancement to HBC5. However, the underlying causes of PSC have not been definitively characterized6.Furthermore, the presence of inflammatory bowel disease (IBD), a persistent inflammatory condition affecting the gastrointestinal tract, particularly ulcerative colitis (UC), has been observed in approximately 70–80% of individuals diagnosed with PSC7, and significantly increases the risk of colorectal cancer to greater than that associated with UC alone8,9.

PSC的自然进展最终导致胆汁性肝硬化的出现，并最终导致肝衰竭，并有可能进一步发展为HBC5。然而，PSC的根本原因尚未明确表征6。此外，在大约70-80%的被诊断患有PSC7的个体中，已经观察到炎症性肠病（IBD）的存在，这是一种影响胃肠道的持续性炎症，特别是溃疡性结肠炎（UC），并且显着增加了结直肠癌的风险，其风险高于单独与UC相关的风险8,9。

Despite the well-established and extensively researched link between PSC and UC, the precise nature of this relationship, in terms of chronological precedence and severity, remains unclear10.Hence, establishing a definitive causal connection between UC and PSC is of paramou.

尽管PSC和UC之间存在公认且广泛研究的联系，但就时间顺序和严重程度而言，这种关系的确切性质仍不清楚10。因此，在UC和PSC之间建立明确的因果关系具有重要意义。

Data availability

数据可用性

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the corresponding author.

评估论文结论所需的所有数据均包含在论文和/或补充材料中。通讯作者可能会要求提供与本文相关的其他数据。

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Download referencesAcknowledgementsWe would like to thank Editage (www.editage.cn) for English language editing.Author informationAuthor notesFangming Wang and Junhui Xiao contributed equally to this work.Authors and AffiliationsDepartment of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410015, Hunan Province, ChinaFangming WangDepartment of Emergency, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410015, ChinaJunhui XiaoAuthorsFangming WangView author publicationsYou can also search for this author in.

下载参考文献致谢我们要感谢Editage（www.Editage.cn）进行英语编辑。作者信息作者注王方明和肖俊辉对这项工作做出了同样的贡献。作者和附属机构湖南省人民医院（湖南师范大学第一附属医院）肝胆外科，湖南长沙，410015，中国王方明湖南省人民医院（湖南师范大学第一附属医院）急诊科，长沙，410015，中国肖俊辉作者王方明观点作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsFangming W: Conceptualization, Formal analysis, Methodology, Writing-original draft, Writing-review & editing; Junhui X: Investigation, Validation, Visualization, Writing-original draft.Corresponding authorCorrespondence to

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Reprints and permissionsAbout this articleCite this articleWang, F., Xiao, J. The mediating role of primary sclerosing cholangitis in the association between ulcerative colitis and hepatobiliary cancer investigated through Mendelian randomization.

转载和许可本文引用本文Wang，F.，Xiao，J。通过孟德尔随机化研究原发性硬化性胆管炎在溃疡性结肠炎和肝胆癌之间的关联中的中介作用。

Sci Rep 14, 31433 (2024). https://doi.org/10.1038/s41598-024-83085-0Download citationReceived: 28 August 2023Accepted: 11 December 2024Published: 28 December 2024DOI: https://doi.org/10.1038/s41598-024-83085-0Share 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.

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Keywordscausal relationshiphepatobiliary cancerMendelian randomizationmediatorprimary sclerosing cholangitisulcerative colitis

关键词胃关系肝胆癌糖尿病随机化介质原发性硬化性胆管炎溃疡性结肠炎