在MASLD中组织学进展和回归的遗传和非遗传驱动因素
Eduardo Vilar-Gomez1, Katherine P Yates2, David E Kleiner3
1Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, IN, United States.
Journal of hepatology
|September 25, 2025
概括
遗传因素和生活方式影响肝病的进展. PNPLA3基因变异会使纤维化恶化,而HSD17B13则提供保护,影响代谢功能障碍相关的脂肪性肝病 (MASLD) 管理.
科学领域:
- 肝病学和遗传流行病学
- 代谢功能障碍相关的稳态性肝病 (MASLD) 发病因子
背景情况:
- 遗传变异与MASLD肝脏组织学进展之间的相互作用尚未完全理解.
- 研究特定的单核酸多态 (SNP),如PNPLA3 rs738409,TM6SF2 rs58542926,和HSD17B13 rs72613567,对于描述疾病轨迹至关重要.
研究的目的:
- 检查PNPLA3,TM6SF2和HSD17B13遗传变异与肝脏组织学纵向变化之间的关联.
- 评估这些SNP对关键组织学结果的影响,包括从MASLD向MASH的进展,纤维化进展和MASH或纤维化的解决.
主要方法:
- 从NASH CRN研究和临床试验中对671个人 (444名成年人,227名儿童) 进行分析,其中至少有两次连续肝活检.
- 使用间隔审查的考克斯模型,根据人口统计和临床因素 (种族,性别,年龄,BMI,T2DM) 进行调整,以评估SNP与组织学结果的关联.
- 开发和分析了3-SNP多基因风险评分 (PRS) 来评估对疾病进展和回归的综合遗传影响.
主要成果:
- PNPLA3 G等位基因与纤维化进展的增加有关 (aHR 1.31).
- HSD17B13 A基因基因表现出保护作用,减轻了MASLD至MASH进展 (aHR 0.46) 和纤维化进展 (aHR 0.69),同时促进了MASH解决 (aHR 1.58) 和纤维化回归 (aHR 1.42).
- 结合风险等位基因的3-SNP PRS预测了组织学进展,而非风险等位基因的PRS与回归有关. 非遗传因素 (T2DM,BMI变化) 和与年龄,性别,BMI和T2DM的相互作用显著改变了这些遗传效应.
结论:
- 遗传倾向,特别是涉及PNPLA3和HSD17B13变体,显著影响MASLD的组织学轨迹.
- 遗传因素与BMI和T2DM等非遗传因素之间的相互作用是MASLD进展和回归的关键驱动因素.
- 这些发现支持对MASLD风险分层和管理的个性化方法,整合遗传和临床信息.
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