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.

中文翻译：

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代谢功能障碍相关脂肪性肝病的遗传学：最新进展


代谢功能障碍相关脂肪性肝病 （MASLD） 遗传学的最新进展正在逐渐揭示该疾病异质性的潜在机制，并在患者分层方面显示出有希望的结果。使用全基因组关联研究、外显子组范围关联研究、表型组范围关联研究和全外显子组测序，该疾病的遗传特征已迅速开发。这些进步是由计算能力的提高、新分析算法的开发（包括一些基于人工智能的算法）以及招募大量且表型良好的队列推动的。本综述介绍了遗传研究的最新进展，强调了来自下一代测序方法的新生物学见解。此外，我们还讨论了发现 MASLD 新遗传位点的创新方法，包括罕见变异。为了全面管理 MASLD ，对风险进行分层非常重要。因此，我们介绍了全表型组关联研究关联的最新信息，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。我们特别关注精准医疗，引入了诸如遗传学与环境之间的相互作用等概念，以通过生活方式或标准疗法调节遗传风险。有一个专门的章节专门介绍基于基因的疗法。讨论了已批准的药理学方法的局限性，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定。