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

doi:10.3969/j.issn.1674-8115.2026.07.015

Abstract

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

CLC Number:

R735.7

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.

Figures/Tables 6

Fig 1 Study design workflow

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

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

Fig 4 MR analysis of immune cell traits associated HCC

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

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

TrendMD

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