Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development.

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports Pub Date : 2025-06-11 eCollection Date: 2025-09-01 DOI:10.1016/j.jhepr.2025.101485

Jonas Ghouse, Helene Gellert-Kristensen, Colm J O'Rourke, Anne-Sofie Seidelin, Gudmar Thorleifsson, Gardar Sveinbjörnsson, Vinicius Tragante, Chigoziri Konkwo, Joseph Brancale, Silvia Vilarinho, Tim M Eyrich, Gustav Ahlberg, Johan S Bundgaard, Søren A Rand, Pia R Lundegaard, Erik Sørensen, Christina Mikkelsen, Jacob Træholt, Christian Erikstrup, Khoa M Dinh, Mie T Bruun, Bitten Aa Jensen, Jakob T Bay, Søren Brunak, Karina Banasik, Henrik Ullum, Triin Laisk, Reedik Mägi, Lincoln D Nadauld, Kirk U Knowlton, Stacey Knight, Lise L Gluud, Kirsten Vistisen, Einar S Björnsson, Magnus O Ulfarsson, Patrick Sulem, Hilma Holm, Ole B Pedersen, Sisse R Ostrowski, Daniel F Gudbjartsson, Thorunn Rafnar, Kari Stefansson, Ulrik Lassen, Hans-Christian Pommergaard, Jens G Hillingsø, Jesper B Andersen, Henning Bundgaard, Stefan Stender

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引用次数: 0

Abstract

Background & aims: The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC.

Methods: We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC.

Results: In meta-analyses totaling 6,540 cases and 2,096,759 controls, we identified 10 associations with HCC, of which five (in KLF15, HSD17B13, APOE, HFE, and MTARC1) have not previously been implicated in HCC at genome-wide statistical significance. Known associations in PNPLA3, TM6SF2, TERT, IFNL4, and HLA-DP1 were confirmed. All associations except KLF15 were validated in independent cohorts totaling 7,630 cases and 733,689 controls. The largest per-allele effect was seen for TM6SF2 (beta = 0.61) followed by PNPLA3 (0.55), HFE (0.45), IFNL4 (0.31), APOE (0.27), HSD17B13, HLA-DP1, and TERT (all 0.21), and MTARC1 (0.17). The identified variants had comparable effects on incident HCC in individuals with prevalent obesity, a high alcohol intake, diabetes, or cirrhosis. Mendelian randomization analyses confirmed the causal role of obesity in HCC. We found strong correlations between genetic effects on HCC and hepatic steatosis (r² = 0.75), and HCC and cirrhosis (r² = 0.69), whereas only three loci (APOE, HFE, and TERT) had concordant effects on HCC and biliary tract cancer.

Conclusions: We identified and validated nine genetic variants associated with an increased risk of HCC development.

Impact and implications: The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.

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全基因组荟萃分析确定了9个与肝细胞癌发展高风险相关的基因座。

背景与目的：肝细胞癌（HCC）的遗传基础在很大程度上仍然未知。因此，我们旨在确定HCC的新的遗传风险位点。方法：我们对11个队列进行了全基因组关联研究（GWAS）荟萃分析，并在两个独立队列中进行了验证。鉴定出的变异对其他肝胆终点的影响，以及对按潜在危险因素分层的HCC发生率的影响。孟德尔随机化用于评估一系列特征对HCC风险的因果影响。结果：在总计6540例病例和2096759例对照的荟萃分析中，我们确定了10个与HCC相关的因素，其中5个（KLF15、HSD17B13、APOE、HFE和MTARC1）之前在全基因组统计学意义上与HCC无关。已知与PNPLA3、TM6SF2、TERT、IFNL4和HLA-DP1相关。除KLF15外的所有关联均在独立队列中得到验证，共7,630例病例和733,689例对照。单个等位基因效应最大的是TM6SF2 (β = 0.61)，其次是PNPLA3（0.55）、HFE（0.45）、IFNL4（0.31）、APOE（0.27）、HSD17B13、HLA-DP1和TERT（均为0.21）和MTARC1（0.17）。已确定的变异对普遍肥胖、高酒精摄入、糖尿病或肝硬化患者的HCC发生率具有相当的影响。孟德尔随机化分析证实了肥胖在HCC中的因果作用。我们发现基因对HCC和肝脂肪变性（r2 = 0.75）、HCC和肝硬化（r2 = 0.69）有很强的相关性，而只有三个位点（APOE、HFE和TERT）对HCC和胆道癌有一致的影响。结论：我们确定并验证了与HCC发展风险增加相关的9种遗传变异。影响和启示：HCC的遗传基础在很大程度上仍然未知。在这项涉及6540例HCC患者和210万对照者的全基因组关联荟萃分析中，我们确定并验证了9个与HCC风险相关的基因位点。更深入地了解影响HCC风险的遗传因素可以提高我们预测并最终预防或治疗这种致命癌症的能力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

12.40

自引率

2.40%

发文量

161

审稿时长

36 days

期刊介绍： JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.