PDF(Pubmed)
Abstract：
Observational studies have shown an association between liver dysfunction and hepatocellular carcinoma (HCC), but the causality relationship between them is unclear. We aimed to determine whether there is a bidirectional causal relationship between liver function indicators (alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; γ-glutamyltransferase, GGT) and HCC. Our two-sample Mendelian randomization (MR) study acquired single nucleotide polymorphisms (SNPs) associated with liver function indicators (ALT, n = 134,182; AST, n = 134,154; GGT, n = 118,309; ALP, n = 105,030) and with HCC (n = 197,611) from publicly available genome-wide association studies (GWAS) of East Asian ancestry in Japan (BioBank Japan, BBJ). Univariable MR analyses were performed to identify whether the genetic evidence of exposure was significantly associated with outcome. Multivariable MR analysis was conducted to estimate the independent effects of exposures on outcome. Univariable MR analysis indicated that the level of ALT, AST, and GGT was the risk factor for HCC incidence. Meanwhile, multivariable MR analysis revealed that AST was an independent risk factor for HCC. The hazard ratio (HR) of the probability of HCC was 3.045 [95% confidence interval (95%CI), 1.697-5.463, p = 0.003] for AST. The results of reverse MR analyses showed that gene-predictive HCC incidence could increase the levels of AST (HR = 1.031, 95%CI: 1.009-1.054, p = 2.52 × 10-4) and ALT (HR = 1.040, 95%CI: 1.019-1.063, p = 0.005). Meanwhile, HCC may be negatively correlated with ALP levels (HR = 0.971, 95%CI: 0.947-0.995, p = 0.018). This study provides evidence to support that genetically predicted higher levels of AST are related to increased risk of HCC, with no strong evidence of a causal effect of genetically predicted ALP, ALP, and GGT on HCC. In addition, genetic predisposition to HCC could influence blood concentration of ALT, AST, and ALP. Thus, this may create a vicious cycle.
摘要：
观察性研究表明，肝功能障碍与肝细胞癌（HCC）之间存在关联，但两者之间的因果关系尚不清楚。我们旨在确定肝功能指标之间是否存在双向因果关系（丙氨酸转氨酶，ALT；天冬氨酸转氨酶，AST；碱性磷酸酶，ALP;γ-谷氨酰转移酶,GGT）和HCC。我们的双样本孟德尔随机化（MR）研究获得了与肝功能指标（ALT，n=134,182；AST，n=134,154；GGT，n=118,309；ALP，n=105,030）和来自日本东亚血统公开可用的全基因组关联研究（GWAS）的HCC（n=197,611）（BioBankJapan，BBJ)。进行了单变量MR分析，以确定暴露的遗传证据是否与结果显着相关。进行多变量MR分析以估计暴露对结果的独立影响。单变量MR分析显示ALT水平,AST,GGT是HCC发病的危险因素。同时,多变量MR分析显示AST是HCC的独立危险因素。HCC发生概率的风险比(HR)为3.045[95%置信区间(95CI),AST为1.697-5.463，p=0.003]。反向MR分析结果表明，基因预测HCC的发生率可增加AST（HR=1.031，95CI：1.009-1.054，p=2.52×10-4）和ALT（HR=1.040，95CI：1.019-1.063，p=0.005）。同时,HCC可能与ALP水平呈负相关(HR=0.971,95CI:0.947-0.995,p=0.018)。这项研究提供了证据，支持基因预测较高水平的AST与HCC风险增加有关。没有强有力的证据表明基因预测的ALP有因果关系，ALP,和GGT在HCC上。此外,肝癌的遗传易感性可影响ALT的血液浓度，AST,ALP。因此，这可能会造成恶性循环。
