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Mendelian Randomization Using a Japanese GWAS Identifies an HLA-Linked Causal Effect of Chronic Hepatitis B on Cholangiocarcinoma Risk.

Khaled Elgeshy·Katsuya Nagaoka·Hajime Yamazaki·Munenori Honda·Maiko Nagaoka·Takahiro Mizuta·Toshinori Toyota·Daiki Maeda·Sotaro Kurano·Kentaro Tanaka·Satoshi Narahara·Hiroki Inada·Takayuki Tokunaga·Etsuko Iio·Takehisa Watanabe·Hiroko Setoyama·Haruki Uojima·Yasuhito Tanaka
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Abstract

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer that develops in the bile ducts. Its incidence is particularly high in East Asian populations, but the underlying genetic factors remain unclear. To investigate potential risk factors for CCA, we conducted a Mendelian randomization study to infer causality. METHODS: Using large-scale genome-wide association study data from the BioBank Japan resource, we systematically investigated the causal effects of genetic predisposition to seven conditions, chronic hepatitis B (CHB), chronic hepatitis C, autoimmune hepatitis, type 1 diabetes, type 2 diabetes, chronic gastritis, and chronic pancreatitis, on CCA risk. RESULTS: Our analysis reveals a significant association between genetic susceptibility to CHB with a 24% higher likelihood of developing CCA than non-susceptible individuals (Inverse-Variance Weighted Odds Ratio = 1.24, 95% Confidence Interval: 1.08-1.42; p = 0.002). This genetic association is significantly driven by instrumental variables enriched in the immune-regulatory HLA class II region (6p21), suggesting a plausible biological mechanism. For the primary outcome (CCA), statistical significance was assessed across seven exposures at a Bonferroni-corrected threshold (two-sided p<0.0071). Notably, the CHB-CCA association remains significant after correction. This primary finding is strongly supported by comprehensive sensitivity analyses that showed no evidence of confounding by horizontal pleiotropy or heterogeneity. Conversely, no significant causal effects on CCA were identified for the other six conditions. CONCLUSIONS: Our MR analysis supports a causal role of HBV infection in CCA development, highlighting the importance of targeted HBV screening and surveillance.

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FemaleHumansMaleBile Duct NeoplasmsCholangiocarcinomaFollow-Up StudiesGenetic Predisposition to DiseaseGenome-Wide Association StudyHepatitis B, ChronicHLA AntigensJapanMendelian Randomization AnalysisPolymorphism, Single NucleotidePrognosisRisk FactorsEast Asian PeopleHepatitis B VirusJapanese populationMendelian randomizationcholangiocarcinomagenome-wide association studyJournal Article

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Khaled Elgeshy, Katsuya Nagaoka, Hajime Yamazaki, Munenori Honda, Maiko Nagaoka, Takahiro Mizuta, Toshinori Toyota, Daiki Maeda, Sotaro Kurano, Kentaro Tanaka, Satoshi Narahara, Hiroki Inada, Takayuki Tokunaga, Etsuko Iio, Takehisa Watanabe, Hiroko Setoyama, Haruki Uojima, Yasuhito Tanaka. 2026-08-01. Mendelian Randomization Using a Japanese GWAS Identifies an HLA-Linked Causal Effect of Chronic Hepatitis B on Cholangiocarcinoma Risk.. https://doi.org/10.31557/apjcp.2026.27.8.2923

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