Background & Aims MRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases. Methods First, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures. Results We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10-8). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective. Conclusion The association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals. Lay summary We estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.

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肝脏 MRI 的全基因组和孟德尔随机化研究对脂肪性肝炎的发病机制有深入的了解

背景和目的 基于 MRI 的校正 T1 (cT1) 是一种非侵入性方法，用于对脂肪性肝炎和肝纤维化的严重程度进行分级。我们旨在确定影响肝脏 cT1 的遗传变异，并使用遗传学来了解肝脏纤维炎症性疾病的潜在机制及其与其他代谢特征和疾病的联系。方法 首先，我们对来自英国生物银行的 14,440 名欧洲人进行了全基因组关联研究 (GWAS)，采用肝脏 cT1 测量。其次，我们探讨了 cT1 变体对肝脏血液检测以及一系列代谢特征和疾病的影响。第三，我们使用孟德尔随机化来测试 24 种主要代谢特征对肝脏 cT1 测量的因果影响。结果 我们确定了 6 个与肝脏 cT1 相关的独立遗传变异，这些变异达到了 GWAS 显着性阈值 (p <5×10-8)。其中四种变体（SLC30A10 中的 rs759359281、SLC39A8 中的 rs13107325、TM6SF2 中的 rs58542926、PNPLA3 中的 rs738409）也与转氨酶升高有关，并对肝脏脂肪和其他代谢特征有不同的影响。胰岛素抵抗、2 型糖尿病、非酒精性脂肪肝和体重指数与 cT1 升高有因果关系，而有利的肥胖（由与较高肥胖相关但心血管代谢疾病风险较低和较低肝脏脂肪相关的变异检测）具有保护作用. 结论 2种金属离子转运体与cT1的关联提示了脂肪性肝炎的重要新机制。未来的研究需要确定针对已识别转运蛋白的干预措施是否可以预防高危人群的肝病。总结 我们根据 14,440 名英国生物银行参与者的磁共振成像估计了肝脏炎症和瘢痕形成的水平。我们进行了一项基因研究，并确定了与肝脏炎症和疤痕水平相关的 6 个基因的变异。其中 4 个基因发生变异的参与者在血液样本中的肝细胞损伤标志物水平也更高，这进一步验证了它们在肝脏健康中的作用。两个已确定的基因参与了我们体内金属离子的运输。对这些变化的进一步研究可能会导致更好地检测、评估和/或治疗肝脏炎症和疤痕。我们进行了一项基因研究，并确定了与肝脏炎症和疤痕水平相关的 6 个基因的变异。其中 4 个基因发生变异的参与者在血液样本中的肝细胞损伤标志物水平也更高，这进一步验证了它们在肝脏健康中的作用。两个已确定的基因参与了我们体内金属离子的运输。对这些变化的进一步研究可能会导致更好地检测、评估和/或治疗肝脏炎症和疤痕。我们进行了一项基因研究，并确定了与肝脏炎症和疤痕水平相关的 6 个基因的变异。其中 4 个基因发生变异的参与者在血液样本中的肝细胞损伤标志物水平也更高，这进一步验证了它们在肝脏健康中的作用。两个已确定的基因参与了我们体内金属离子的运输。对这些变化的进一步研究可能会导致更好地检测、评估和/或治疗肝脏炎症和疤痕。