Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK.
Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK; Perspectum Diagnostics Ltd., Oxford, UK.
J Hepatol. 2020 Aug;73(2):241-251. doi: 10.1016/j.jhep.2020.03.032. Epub 2020 Apr 2.
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.
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.
We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10). 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.
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.
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.
基于磁共振成像的校正 T1 值（cT1）是一种非侵入性方法，可用于对脂肪性肝炎和肝纤维化的严重程度进行分级。我们旨在鉴定影响肝脏 cT1 的遗传变异，并利用遗传学来了解肝纤维炎症性疾病的发病机制及其与其他代谢特征和疾病的关联。
首先，我们在英国生物库中进行了一项针对 14440 名欧洲人的全基因组关联研究（GWAS），研究对象的肝脏 cT1 值可通过磁共振成像进行测量。其次，我们探索了 cT1 变异对肝脏血液检查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检验了 24 种主要代谢特征对肝脏 cT1 值的因果效应。
我们鉴定出 6 个与肝脏 cT1 相关的独立遗传变异，这些变异达到了全基因组关联研究的显著性阈值（p < 5×10）。其中 4 个变异（SLC30A10 中的 rs759359281、SLC39A8 中的 rs13107325、TM6SF2 中的 rs58542926、PNPLA3 中的 rs738409）也与转氨酶升高相关，并且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、非酒精性脂肪性肝病和体重指数与 cT1 升高呈因果关系，而有利的肥胖（通过与更高的肥胖相关但与心血管代谢疾病和更低的肝脏脂肪风险较低的变异来确定）被发现具有保护作用。
2 种金属离子转运蛋白与 cT1 的关联表明，在脂肪性肝炎中存在一个重要的新机制。未来的研究需要确定针对鉴定出的转运蛋白的干预措施是否可能预防高危人群的肝脏疾病。
我们根据英国生物库中 14440 名参与者的磁共振成像估计了肝脏炎症和纤维化的程度。我们进行了一项遗传研究，鉴定出与肝脏炎症和纤维化程度相关的 6 个基因的变异。在这 4 个基因中，有变异的参与者的血液样本中肝细胞损伤的标志物水平也更高，进一步验证了它们在肝脏健康中的作用。鉴定出的 2 个基因与我们体内金属离子的转运有关。对这些变异的进一步研究可能会导致更好地检测、评估和/或治疗肝脏炎症和纤维化。
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