人们对脂肪肝病与心血管和癌症结果之间联系的潜在机制知之甚少。我们的目标是使用 MRI 衍生的肝脏脂肪和遗传学测量来研究将较高的肝脏脂肪与各种健康结果联系起来的因果机制。我们对 37,358 名英国生物银行参与者进行了一项全基因组关联研究，以确定与肝脏脂肪相关的遗传变异核磁共振扫描。我们使用孟德尔随机化方法，利用已发表的 GWAS 和 FinnGen 的数据，研究肝脏脂肪对健康结果的因果影响，与 BMI、饮酒量和血脂无关。我们确定了 13 种与肝脏脂肪相关的遗传变异，这些变异对健康结果显示出不同的风险。与肝甘油三酯输出受损相关的遗传变异表明，肝脏脂肪增加等位基因与冠状动脉疾病和心肌梗塞风险降低相关，但与 2 型糖尿病风险升高相关；与增强从头脂肪生成相关的变异表明，肝脏脂肪增加等位基因与心肌梗塞和冠状动脉疾病的较高风险有关。遗传上较高的肝脏脂肪含量会增加非酒精性肝硬化、肝细胞癌、肝内胆管癌和胆囊癌的风险，无论机制如何，都表现出剂量依赖性关系。这项研究为肝脏脂肪对健康的异质性影响提供了新的见解结果。它挑战了肝脏脂肪本身是心血管疾病的独立危险因素的观念，强调了这种关联对驱动肝脏脂肪积累的特定机制的依赖性。然而，无论如何实现，过量的肝脏脂肪似乎都以剂量依赖性方式与肝硬化和癌症存在因果关系。这项研究增进了我们对影响肝脏脂肪积累机制的异质性的理解，为肝脏脂肪积累如何积累提供了新的见解。可能会影响各种健康结果。这些发现挑战了肝脏脂肪是心血管疾病的独立危险因素的观点，并强调了一些遗传变异对脂肪积累和心血管疾病发展的机制影响。这项研究对于包括医生、研究人员以及患者在内的医疗保健专业人员特别重要，因为它可以通过了解肝脏脂肪与各种健康结果之间的关系来进行更有针对性和个性化的治疗。研究结果强调需要个性化的管理方法和重塑风险评估标准。它还为优先考虑旨在减少肝脏脂肪含量的临床干预提供了空间（然而，可能是通过有意减肥实现的），这有助于预防与肝脏相关的纤维化和癌症。版权所有 © 2024。由 Elsevier B.V. 出版。

The underlying mechanisms for the link between steatotic liver disease and cardiovascular and cancer outcomes are poorly understood. We aimed to use MRI-derived measures of liver fat and genetics to investigate causal mechanisms that link higher liver fat to various health outcomes.We conducted a genome-wide association study on 37,358 UK Biobank participants to identify genetic variants associated with liver fat measured from MRI scans. We used Mendelian randomization approach to investigate the causal effect of liver fat on health outcomes independent of BMI, alcohol consumption and lipids using data from published GWAS and FinnGen.We identified 13 genetic variants associated with liver fat that showed differing risks to health outcomes. Genetic variants associated with impaired hepatic triglyceride export showed liver fat-increasing alleles to be correlated with a reduced risk of coronary artery disease and myocardial infarction but an elevated risk of type 2 diabetes; and variants associated with enhanced de novo lipogenesis showed liver fat-increasing alleles to be linked to a higher risk of myocardial infarction and coronary artery disease. Genetically higher liver fat content increased the risk of non-alcohol liver cirrhosis, hepatocellular and Intrahepatic bile ducts and gallbladder cancers, exhibiting a dose-dependent relationship, irrespective of the mechanism.This study provides fresh insight into the heterogeneous effect of liver fat on health outcomes. It challenges the notion that liver fat per se is an independent risk factor for cardiovascular disease, underscoring the dependency of this association on the specific mechanisms that drive fat accumulation in the liver. However, excess liver fat, regardless of how achieved, appears to be causally linked to liver cirrhosis and cancers in a dose dependent manner.This research advances our understanding of the heterogeneity in mechanisms influencing liver fat accumulation, providing new insights into how liver fat accumulation may impact various health outcomes. The findings challenge the notion that liver fat is an independent risk factor for cardiovascular disease and highlight the mechanistic effect of some genetic variants on fat accumulation and the development of cardiovascular diseases. This study is of particular importance for healthcare professionals including physicians and researchers as well as patients as it allows for more targeted and personalised treatment by understanding the relationship between liver fat and various health outcomes. The findings emphasise the need for a personalised management approach and a reshaping of risk assessment criteria. It also provides room for prioritising a clinical intervention aimed at reducing liver fat content (likely by intentional weight loss, however, achieved) that could help protect against liver related fibrosis and cancer.Copyright © 2024. Published by Elsevier B.V.