Kubina Matthew, Prasitsumrit Vitchapong, Tan Jarell, Quek Joo Wei Ethan, Peddu Dhiraj, Mishra Ankit, Danpanichkul Pojsakorn, Mann Jake P, Trépo Eric, Buch Stephan, Huang Daniel Q, Ng Cheng Han, Muthiah Mark D, Wong Yu Jun, Wijarnpreecha Karn, Chen Vincent L
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
Aliment Pharmacol Ther. 2025 Aug;62(3):244-276. doi: 10.1111/apt.70256. Epub 2025 Jun 28.
Genetic variants associated with risk of steatotic liver disease (SLD) may also influence clinical events.
To perform a systematic review and meta-analysis to determine the impact of SLD-associated genetic variants on hepatic and extrahepatic complications in SLD.
We searched PubMed, Embase and Medline databases from inception through July 4th, 2024 for studies on adults with SLD that reported effects of PNPLA3, TM6SF2, MBOAT7, HSD17B13 and GCKR variants on the incidence of cirrhosis, major adverse liver outcomes (MALO), cardiovascular disease, extrahepatic malignancy and overall or cause-specific mortality. We pooled hazard ratios and 95% confidence intervals from these outcomes to allow for comparison.
We screened 6475 studies and included 40 in the final analysis. PNPLA3-rs738409-GG genotype (vs. CC genotype) was associated with significantly higher incidence of MALO (sHR 2.30 [95% CI 1.66-3.18]), liver-related mortality (sHR 2.83 [95% CI 1.58-5.06]) and all-cause mortality (HR 1.24 [95% CI 1.04-1.47]). TM6SF2-rs58542926-CT or TT (vs. CC) genotype was associated with a higher incidence of hepatocellular carcinoma (sHR 2.12 [95% CI 1.66-2.70]). MALO was significantly associated with MBOAT7 -rs641738-TT (vs. CC) genotype (sHR 1.21 [95% CI 1.1-1.33]). Limitations in the literature include inconsistent outcome reporting and distribution of fibrosis stage, and a relative paucity of studies on both alcohol-associated liver disease and non-PNPLA3 genetic variants.
Variants in PNPLA3, TM6SF2 and MBOAT7 are significantly associated with hepatic outcomes, especially with advanced baseline liver disease, with modest effects on extrahepatic outcomes. Routine genotyping may improve risk stratification in SLD patients with advanced liver disease.
与脂肪性肝病（SLD）风险相关的基因变异也可能影响临床事件。
进行系统综述和荟萃分析，以确定与SLD相关的基因变异对SLD患者肝脏和肝外并发症的影响。
我们检索了从数据库建立至2024年7月4日的PubMed、Embase和Medline数据库，以查找关于成年SLD患者的研究，这些研究报告了PNPLA3、TM6SF2、MBOAT7、HSD17B13和GCKR基因变异对肝硬化发病率、主要不良肝脏结局（MALO）、心血管疾病、肝外恶性肿瘤以及全因死亡率或病因特异性死亡率的影响。我们汇总了这些结局的风险比和95%置信区间，以便进行比较。
我们筛选了6475项研究，最终纳入40项进行分析。PNPLA3基因的rs738409位点GG基因型（与CC基因型相比）与MALO的显著更高发病率（标准化风险比[sHR] 2.30 [95%置信区间1.66 - 3.18]）、肝脏相关死亡率（sHR 2.83 [95%置信区间1.58 - 5.06]）和全因死亡率（风险比[HR] 1.24 [95%置信区间1.04 - 1.47]）相关。TM6SF2基因的rs58542926位点CT或TT基因型（与CC基因型相比）与肝细胞癌的更高发病率相关（sHR 2.12 [95%置信区间1.66 - 2.70]）。MALO与MBOAT7基因的rs641738位点TT基因型（与CC基因型相比）显著相关（sHR 1.21 [95%置信区间1.1 - 1.33]）。文献中的局限性包括结局报告不一致和纤维化分期分布不均，以及酒精性肝病和非PNPLA3基因变异的研究相对较少。
PNPLA3、TM6SF2和MBOAT7基因的变异与肝脏结局显著相关，尤其是与基线肝病晚期相关，对肝外结局影响较小。常规基因分型可能改善晚期肝病SLD患者的风险分层。
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