Clinical and Molecular Hepatology, Translational Health Research Center (CENITRES), Maimónides University, Buenos Aires, Argentina; Faculty of Health Science, Maimónides University, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Clin Gastroenterol Hepatol. 2024 Nov;22(11):2177-2187.e3. doi: 10.1016/j.cgh.2024.05.052. Epub 2024 Jul 31.
Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome-wide association studies, exome-wide association studies, phenome-wide association studies, and whole exome sequencing. These advances have been powered by the increase in computational power, the development of new analytical algorithms, including some based on artificial intelligence, and the recruitment of large and well-phenotyped cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on phenome-wide association study associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）遗传研究的最新进展逐渐揭示了该疾病异质性的发生机制，并在患者分层方面取得了有前景的结果。采用全基因组关联研究、外显子组关联研究、表型组关联研究和全外显子测序对疾病进行遗传特征分析。这些进展得益于计算能力的提高、新分析算法的发展，包括一些基于人工智能的算法，以及大型、表型良好的队列的招募。本文综述了遗传研究的最新进展，强调了下一代测序方法带来的新生物学见解。此外，我们还讨论了用于发现 MASLD 新遗传位点的创新方法，包括罕见变异。为了全面管理 MASLD，对风险进行分层很重要。因此，我们介绍了表型组关联研究关联的最新进展，包括极端表型。此外，我们还讨论了多基因风险评分和靶向测序是否已准备好用于临床应用。特别关注精准医学，我们引入了遗传与环境相互作用的概念，以调节生活方式或标准治疗的遗传风险。还有一个专门的章节介绍基因治疗。讨论了已批准的药物治疗方法的局限性，并回顾了基因相关机制在治疗开发中的潜力，包括对 MASLD 患者进行基因检测的决策。
