胰高血糖素样肽-1作用与代谢性肝病相关性的遗传分析：孟德尔随机化分析的见解
Genetic analysis of the correlation between GLP1 action and metabolic liver disease: Insights from Mendelian randomization analysis.
作者信息
Ma Zhiqiang, Wang Binyu, Li Danpei, Chen Xi
机构信息
Division of Cardiology, Department of Internal Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
出版信息
J Diabetes Investig. 2025 Aug;16(8):1409-1419. doi: 10.1111/jdi.70087. Epub 2025 Jun 1.
PURPOSE
Previous studies have shown that glucagon-like peptide 1 (GLP1) receptor agonists may help improve metabolic dysfunction-associated steatotic liver disease (MASLD), but supportive genetic data remain limited. Our study aims to explore the correlation between GLP1 action and MASLD.
METHODS
Mendelian randomization (MR) was performed, with 22 cis-eQTLs and 2 missense mutations used as proxies for GLP1 action. MASLD data from the FinnGen study served as the primary analysis, with replication in an independent cohort. Subsequently, mediation analyses were conducted to explore the role of MASLD risk factors in the correlation between GLP1 action and MASLD. Finally, phenome-wide association studies (Phe-WAS) were performed.
RESULTS
Using cis-eQTLs as exposure, genetically predicted GLP1 action was associated with a decreased risk of MASLD in the primary analysis [IVW: odds ratio (OR): 0.36; 95% confidence interval (CI): 0.30-0.44; P = 1.37E-22] and in the replication study (IVW: OR: 0.61; 95% CI: 0.47-0.81; P = 5.58E-04). In mediation analyses, the proportion of the mediation effect of GLP1 action via type 2 diabetes was 6% (95% CI: 0.0004-0.1138; P = 4.70E-02), via hypertension was 4% (95% CI: 0.0128-0.0675; P = 3.82E-03), while via high-density lipoprotein cholesterol was 1% (95% CI: 0.0039-0.0187; P = 2.52E-03). Using missense mutations as exposure, no causal relationship between GLP1 action and MASLD was observed. Phe-WAS showed cardiovascular and renal benefits of GLP1 action.
CONCLUSIONS
Our genetic analysis suggests a possible causal relationship between GLP1 action and MASLD.
目的
既往研究表明，胰高血糖素样肽1（GLP1）受体激动剂可能有助于改善代谢功能障碍相关脂肪性肝病（MASLD），但支持性的遗传学数据仍然有限。我们的研究旨在探索GLP1作用与MASLD之间的相关性。
方法
进行孟德尔随机化（MR）分析，使用22个顺式表达数量性状基因座（cis-eQTL）和2个错义突变作为GLP1作用的代理变量。来自芬兰基因研究（FinnGen study）的MASLD数据作为主要分析对象，并在一个独立队列中进行重复验证。随后，进行中介分析以探讨MASLD危险因素在GLP1作用与MASLD相关性中的作用。最后，进行全表型关联研究（Phe-WAS）。
结果
在主要分析中，以顺式表达数量性状基因座作为暴露因素，遗传预测的GLP1作用与MASLD风险降低相关[逆方差加权法（IVW）：比值比（OR）：0.36；95%置信区间（CI）：0.30-0.44；P = 1.37×10⁻²²]，在重复研究中也得到了类似结果（IVW：OR：0.61；95% CI：0.47-0.81；P = 5.58×10⁻⁴）。在中介分析中，GLP1作用通过2型糖尿病的中介效应比例为6%（95% CI：0.0004-0.1138；P = 4.70×10⁻²），通过高血压的中介效应比例为4%（95% CI：0.0128-0.0675；P = 3.82×10⁻³），而通过高密度脂蛋白胆固醇的中介效应比例为1%（95% CI：0.0039-0.0187；P = 2.52×10⁻³）。以错义突变作为暴露因素时，未观察到GLP1作用与MASLD之间存在因果关系。全表型关联研究显示GLP1作用对心血管和肾脏有益。
结论
我们的遗传分析表明GLP1作用与MASLD之间可能存在因果关系。
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