Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
J Hepatol. 2018 Feb;68(2):268-279. doi: 10.1016/j.jhep.2017.09.003. Epub 2017 Nov 6.
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.
非酒精性脂肪性肝病（NAFLD）现已被认为是全球最常见的肝脏疾病。它涵盖了广泛的疾病谱，从单纯性脂肪变性，到非酒精性脂肪性肝炎，再到纤维化，最终发展为肝硬化和肝细胞癌。NAFLD 的一个显著特点是疾病进展在患者间存在很大的差异。NAFLD 被认为是一种复杂的疾病特征，即环境与易感多基因宿主背景之间的相互作用决定了疾病表型，并影响疾病的进展。近年来，已经进行了多次全基因组关联和大型候选基因研究，这丰富了我们对 NAFLD 遗传基础的理解。值得注意的是，I148M PNPLA3 变异被确定为 NAFLD 的主要常见遗传决定因素。TM6SF2、MBOAT7 和 GCKR 中的中等效应大小变体也被证明具有显著贡献。本文的研究前提是讨论 NAFLD 进展的重要遗传和表观遗传修饰因子的研究现状。将积累的遗传数据转化为新型治疗药物的设计和诊断/预后生物标志物的临床实施的潜力将得到探讨。最后，将阐述和讨论个体化医学以及后遗传学时代的未来研究机会和挑战。
