Speliotes Elizabeth K, Schneider Carolin Victoria
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Liver Int. 2025 Mar;45(3):e16106. doi: 10.1111/liv.16106. Epub 2024 Nov 19.
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression.
We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists.
The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers.
The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.
代谢功能障碍相关脂肪性肝病（MASLD）影响着高达30%的西方人群。虽然肥胖是一个公认的风险因素，但并非所有肥胖个体都会患上MASLD，这凸显了理解基因与环境相互作用的必要性。PNPLA3 I148M变异已被确定为关键的遗传风险因素，显著增加了MASLD发生和进展的可能性。
我们回顾了当前关于PNPLA3 I148M在MASLD中作用的文献，重点关注涉及饮食、体育活动、肥胖和胰岛素抵抗的基因-环境相互作用。我们纳入了分析PNPLA3 I148M患病率的种族差异及其与MASLD关联的研究。此外，我们还回顾了关于PNPLA3 I148M如何影响对治疗的反应的数据，包括降脂药物和胰高血糖素样肽-1（GLP-1）激动剂。
PNPLA3 I148M变异显著增加了MASLD风险，尤其是在西班牙裔人群中，该人群中MASLD的患病率较高。高糖摄入、饮酒和缺乏体育活动等生活方式因素会加剧I148M携带者患MASLD的风险。有证据表明，胰岛素抵抗会放大与I148M变异相关的MASLD风险，尤其是在非糖尿病个体中。此外，PNPLA3 I148M变异与其他基因位点相互作用，进一步改变MASLD风险和疾病进程。该变异还影响治疗反应，携带者中降脂疗法和GLP-1激动剂的有效性存在差异。
PNPLA3 I148M与环境因素之间的相互作用强调了制定个性化MASLD预防和治疗策略的必要性。针对遗传因素和生活方式因素可能会加强MASLD的管理，提供一种量身定制的方法来减轻疾病负担。
