The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
School of Public Health, The Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Cancer Rep (Hoboken). 2024 Jan;7(1):e1913. doi: 10.1002/cnr2.1913. Epub 2023 Oct 16.
The positive relationships of non-alcoholic fatty liver disease (NAFLD) and cirrhosis with liver cancer were shown in previous observational studies, while further Mendelian randomization (MR) investigations are needed to confirm the possible causal associations.
This study aimed to explore whether NAFLD and cirrhosis were causally related to liver cancer using MR in European and East Asian populations.
For European populations, NAFLD data were obtained from a genome-wide meta-analysis (8434 patients and 770 180 controls). The data on chronic elevation of alanine aminotransferase (cALT), a proxy of NAFLD, were derived from Million Veteran Program (68 725 patients and 95 472 controls). Cirrhosis data were collected from two sources: a genome-wide association study of five cohorts (4829 patients and 72 705 controls) and FinnGen (1931 patients and 216 861 controls). Liver cancer data were collected from FinnGen (304 patients and 174 006 controls). For East Asian populations, the data on cirrhosis (2184 patients and 210 269 controls) and hepatocellular carcinoma (1866 patients and 195 745 controls) were obtained from Biobank Japan. Three, 41, seven, six, and three single-nucleotide polymorphisms were used for NAFLD (European), cALT (European), cirrhosis (European-five cohorts), cirrhosis (European-FinnGen), and cirrhosis (East Asian), respectively. We used inverse-variance weighted as the primary method to calculate the odds ratio (OR) and 95% confidence interval (CI). Among European populations, genetically-predicted NAFLD, cALT, cirrhosis (five cohorts), and cirrhosis (FinnGen) were positively associated with liver cancer, with ORs (95% CIs) of 6.62 (3.81-11.50) (p < .001), 2.59 (1.70-3.94) (p < .001), 3.38 (2.41-4.75) (p < .001), and 2.62 (1.20-5.72) (p = .015). Among East Asian populations, there was also a positive association between genetically-predicted cirrhosis and hepatocellular carcinoma (OR = 2.12; 95% CI = 1.78-2.52; p < .001).
This study utilized MR to complementarily confirm the positive connections of NAFLD and cirrhosis with liver cancer, as identified in earlier observational research. Subsequent MR investigations involving more liver cancer cases are needed.
非酒精性脂肪性肝病 (NAFLD) 和肝硬化与肝癌之间的正相关关系在先前的观察性研究中得到了证实，而进一步的孟德尔随机化 (MR) 研究仍需要证实这些可能的因果关联。
本研究旨在通过欧洲和东亚人群的 MR 研究，探讨 NAFLD 和肝硬化是否与肝癌存在因果关系。
对于欧洲人群，NAFLD 数据来自全基因组荟萃分析（8434 例患者和 770180 例对照）。慢性丙氨酸氨基转移酶升高（cALT）的代表数据来源于百万退伍军人计划（68725 例患者和 95472 例对照）。肝硬化数据来自两个来源：五个队列的全基因组关联研究（4829 例患者和 72705 例对照）和 FinnGen（1931 例患者和 216861 例对照）。肝癌数据来自 FinnGen（304 例患者和 174006 例对照）。对于东亚人群，肝硬化（2184 例患者和 210269 例对照）和肝细胞癌（1866 例患者和 195745 例对照）的数据来自日本生物银行。使用了三个、41 个、七个、六个和三个单核苷酸多态性来分别代表欧洲人群的 NAFLD、cALT、肝硬化（欧洲五个队列）、肝硬化（欧洲 FinnGen）和肝硬化（东亚）。我们使用逆方差加权作为主要方法来计算比值比（OR）和 95%置信区间（CI）。在欧洲人群中，遗传预测的 NAFLD、cALT、肝硬化（五个队列）和肝硬化（FinnGen）与肝癌呈正相关，OR（95%CI）分别为 6.62（3.81-11.50）（p<0.001）、2.59（1.70-3.94）（p<0.001）、3.38（2.41-4.75）（p<0.001）和 2.62（1.20-5.72）（p=0.015）。在东亚人群中，遗传预测的肝硬化与肝细胞癌也呈正相关（OR=2.12；95%CI=1.78-2.52；p<0.001）。
本研究利用 MR 研究补充证实了非酒精性脂肪性肝病和肝硬化与肝癌之间的正相关关系，这与先前的观察性研究结果一致。需要更多的肝癌病例进行后续的 MR 研究。
