免疫细胞特征介导酒精性肝病与原发性肝细胞癌的关联：一项孟德尔随机化研究和中介分析

doi:10.3969/j.issn.1674-8115.2026.07.015

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (7): 961-971.doi: 10.3969/j.issn.1674-8115.2026.07.015

• 论著 · 循证医学 • 上一篇

免疫细胞特征介导酒精性肝病与原发性肝细胞癌的关联：一项孟德尔随机化研究和中介分析

郝风节¹^,², 王俊青¹^,²(), 陆晔¹()

^1.上海交通大学医学院附属瑞金医院普外科，上海 200025
^2.上海消化外科研究所，上海 200025

收稿日期:2025-12-22 接受日期:2026-02-24 出版日期:2026-06-29 发布日期:2026-06-29
通讯作者: 陆　晔，主治医师，博士；电子信箱：eric_luye@163.com。
王俊青，主任医师，博士；电子信箱：wangjunqingmd@hotmail.com。
基金资助:
国家自然科学基金面上项目(82372603);国家自然科学基金面上项目(82172900);国家自然科学基金面上项目(82570742);上海市自然科学基金面上项目(24ZR1446500);上海市东方英才拔尖(BJJY2024068);上海交通大学医学院“双百人”项目(20191901);上海消化外科研究所开放课题

Immune cell traits mediate the association between alcoholic liver disease and hepatocellular carcinoma: a Mendelian randomization and mediation analysis

Hao Fengjie¹^,², Wang Junqing¹^,²(), Lu Ye¹()

^1.Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
^2.Shanghai Institute of Digestive Surgery, Shanghai 200025, China

Received:2025-12-22 Accepted:2026-02-24 Online:2026-06-29 Published:2026-06-29
Contact: Lu Ye, E-mail: eric_luye@163.com.
Wang Junqing, E-mail: wangjunqingmd@ hotmail.com.
Supported by:
National Natural Science Foundation of China(82372603);Shanghai Natural Science Foundation(24ZR1446500);Shanghai Oriental Talent Program—Top Talents(BJJY2024068);“Two-hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20191901);Open Project of Shanghai Institute of Digestive Surgery

摘要/Abstract

摘要：

目的·从遗传层面探究酒精性肝病（alcoholic liver disease，ALD）相关基因是否通过调控系统性免疫表型影响肝细胞癌（hepatocellular carcinoma，HCC）风险。方法·采用多步孟德尔随机化（Mendelian randomization，MR）与中介分析结合的研究设计。首先，整合来自eQTLGen联盟的全血顺式表达数量性状基因座（cis-expression quantitative trait loci，cis-eQTL）数据、京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）数据库中ALD相关基因集以及HCC的全基因组关联研究（genome-wide association study，GWAS）汇总数据。筛选与HCC存在单向因果关联的ALD相关基因。工具变量筛选标准设定为全基因组显著性水平、连锁不平衡聚类，并通过计算F统计量排除弱工具变量。其次，针对731种外周血免疫细胞特征展开MR分析，以鉴定与HCC风险相关的免疫表型。最后，通过两步MR中介分析，检验基因是否通过免疫表型介导对HCC产生风险效应。结果·研究筛选出4个与HCC存在稳健因果关联的ALD相关基因：过氧化物酶体增殖物激活受体γ辅激活因子1A（peroxisome proliferator-activated receptor γ coactivator 1-α，PPARGC1A）、丝裂原活化蛋白激酶激酶激酶7（mitogen-activated protein kinase kinase kinase 7，MAP3K7）、乙醛脱氢酶2（aldehyde dehydrogenase 2，ALDH2）和受体相互作用丝氨酸/苏氨酸蛋白激酶1（receptor-interacting serine/threonine-protein kinase 1，RIPK1），其中ALDH2和MAP3K7升高HCC风险，PPARGC1A和RIPK1则降低HCC风险。所有敏感性分析均未发现显著的水平多效性或异质性。此外，还发现23种与HCC风险存在因果关联的外周血免疫细胞特征，涵盖B细胞、CD8⁺ T细胞、CD4⁺ T细胞、调节性T细胞及髓系细胞等谱系。中介分析揭示了2条具体路径：遗传预测PPARGC1A基因部分通过增加CD8dim AC细胞来降低HCC风险；ALDH2基因对HCC的风险部分被初始型CD28⁺ CD45RA⁺ CD8dim%T细胞的增加所抵消。结论·部分ALD相关的HCC遗传风险并非直接作用于肝脏，而是由特定基因改变系统性免疫稳态所介导。该研究为“ALD-免疫-HCC”发病调控轴提供了源于人类群体的因果遗传学证据，并提示上述基因及相关免疫表型可作为潜在的早期预警生物标志物和干预靶点，为针对不同遗传背景人群的精准预防策略提供理论依据。

关键词: 酒精性肝病, 肝细胞癌, 免疫表型, 孟德尔随机化, 中介分析, 生物标志物

Abstract:

Objective ·To explore at the genetic level whether genes related to alcoholic liver disease (ALD) affect the risk of hepatocellular carcinoma (HCC) by regulating systemic immune phenotypes. Methods ·A study design combining multi-step Mendelian randomization (MR) and mediation analysis was adopted. First, cis-expression quantitative trait loci (cis-eQTL) data from the eQTLGen Consortium, ALD-related gene set from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and genome-wide association study (GWAS) summary data for HCC were integrated to identify ALD-related genes with unidirectional causal associations with HCC. Instrumental variable selection criteria included genome-wide significance thresholds, linkage disequilibrium clumping, and F-statistic calculation to exclude weak instruments. Second, MR analysis was performed on 731 peripheral blood immune cell traits to identify immune phenotypes causally associated with HCC risk. Finally, a two-step MR mediation analysis was carried out to test whether genetic effects on HCC risk were mediated through these immune phenotypes. Results ·The study identified 4 ALD-related genes [peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A), mitogen-activated protein kinase kinase kinase 7 (MAP3K7), aldehyde dehydrogenase 2 (ALDH2), and receptor-interacting serine/threonine protein kinase 1 (RIPK1)] with robust causal associations with HCC. Among them, ALDH2 and MAP3K7 increased HCC risk, while PPARGC1A and RIPK1 were protective. All sensitivity analyses revealed no evidence of horizontal pleiotropy or heterogeneity. Additionally, 23 peripheral blood immune cell traits were identified as being causally associated with HCC risk, involving B cells, CD8⁺ T cells, CD4⁺ T cells, regulatory T cells, and myeloid cells. Mediation analysis revealed two specific pathways: genetically predicted PPARGC1A expression partially reduced HCC risk via increased CD8dim AC cells, while the risk effect of ALDH2 on HCC was partially offset by increased naïve CD28⁺ CD45RA⁺ CD8dim %T cells. Conclusion ·Part of the ALD-related genetic risk for HCC is mediated by specific genes that alter systemic immune homeostasis. The study provides human population-based causal genetic evidence for the “ALD-immune-HCC” axis and suggests that the aforementioned genes and related immune phenotypes may serve as potential early-warning biomarkers and therapeutic targets, offering a theoretical basis for precision prevention strategies across different genetic backgrounds.

Key words: alcoholic liver disease, hepatocellular carcinoma, immune phenotype, Mendelian randomization, mediation analysis, biomarker

中图分类号:

R735.7

郝风节, 王俊青, 陆晔. 免疫细胞特征介导酒精性肝病与原发性肝细胞癌的关联：一项孟德尔随机化研究和中介分析[J]. 上海交通大学学报（医学版）, 2026, 46(7): 961-971.

Hao Fengjie, Wang Junqing, Lu Ye. Immune cell traits mediate the association between alcoholic liver disease and hepatocellular carcinoma: a Mendelian randomization and mediation analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(7): 961-971.

图/表 6

图1 研究设计流程

Fig 1 Study design workflow

图2 cis-eQTL数据对HCC的MR分析阳性结果Note： A. Circular plot was used to illustrate results from five MR methods. B. Volcano plot was employed to present positive genes identified from MR analysis.

Fig 2 Positive results from MR analysis of cis-eQTL data on HCC

图3 ALD相关基因对HCC影响的MR分析Note： A. MR analysis using ALD-related genes as exposure and HCC as outcome. B. Reverse MR analysis using HCC as exposure and ALD-related genes as outcome.

Fig 3 MR analysis of the effect of ALD-related genes on HCC

图4 免疫细胞特征对HCC影响的MR分析

Fig 4 MR analysis of immune cell traits associated HCC

图5 ALD相关基因和免疫细胞特征的散点图Note： A. Positive association between PPARGC1A and IgD⁺ CD24⁺ AC. B. Negative association between ALDH2 and CD33br HLA DR⁺ CD14⁻ %CD33br HLA DR⁺. C. Positive association between PPARGC1A and CD8dim AC. D. Negative association between MAP3K7 and CD4⁺ CD8dim AC. E. Negative association between MAP3K7 and CD4⁺ CD8dim % leukocytes. F. Positive association between ALDH2 and CD28⁺ CD45RA⁺ CD8dim %T cells. G. Positive association between MAP3K7 and CD20 on memory B cells. H. Negative association between ALDH2 and CD38 on CD3⁻ CD19⁻. I. Negative association between MAP3K7 and CD66b on Gr MDSC.

Fig 5 Scatter plots of ALD-related genes and immune cell traits

图6 特定免疫细胞表型对ALD到HCC风险的中介效应Note： A. CD8dim AC cells mediate the protective effect of PPARGC1A on HCC risk. B. CD28⁺ CD45RA⁺ CD8dim %T cells mediate the risk effect of ALDH2 on HCC.

Fig 6 Mediating effects of specific immune cell phenotypes on the association between ALD and HCC risk

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免疫细胞特征介导酒精性肝病与原发性肝细胞癌的关联：一项孟德尔随机化研究和中介分析

Immune cell traits mediate the association between alcoholic liver disease and hepatocellular carcinoma: a Mendelian randomization and mediation analysis

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