基于遗传预测的氨基酸血浆水平与代谢相关脂肪性肝病风险：一项孟德尔随机化研究。
Genetically predicted plasma levels of amino acids and metabolic dysfunction-associated fatty liver disease risk: a Mendelian randomization study.
机构信息
The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China.
出版信息
BMC Med. 2023 Nov 28;21(1):469. doi: 10.1186/s12916-023-03185-y.
BACKGROUND
Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk.
METHODS
We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways.
RESULTS
We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13-1.81) and lower glutamine (OR = 0.83, 95% CI 0.73-0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings.
CONCLUSIONS
Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.
背景
新兴的基于代谢组学的研究表明，氨基酸代谢与代谢相关脂肪性肝病（MAFLD）风险之间存在关联；然而，氨基酸代谢在 MAFLD 发展中的病因作用尚不清楚。本研究旨在评估循环氨基酸水平与 MAFLD 风险之间的因果关系。
方法
我们使用全基因组关联研究（GWAS）的汇总水平数据进行了两样本 Mendelian 随机化（MR）分析，以评估遗传预测的循环氨基酸水平与 MAFLD 风险之间的因果关系。在发现 MR 分析中，我们使用了最大的 MAFLD GWAS 数据（8434 例病例和 770180 例对照），而在复制 MR 分析中，我们使用了 MAFLD GWAS 数据（1483 例病例和 17781 例对照），其中 MAFLD 病例是通过肝活检诊断的。我们在 MR 主要分析中使用 Wald 比或逆方差加权（IVW）方法，在敏感性分析中使用加权中位数和 MR-Egger 回归分析。此外，我们通过将遗传工具限制在直接参与氨基酸代谢途径的工具上，进行了保守的 MR 分析。
结果
根据 MR 主要和保守分析的结果，我们发现遗传预测的较高水平的丙氨酸（OR=1.43，95%CI 1.13-1.81）和较低的谷氨酰胺（OR=0.83，95%CI 0.73-0.96）与 MAFLD 的发病风险增加相关。MR 敏感性分析和使用质子密度脂肪分数作为连续结果代理 MAFLD 的补充分析的结果支持了主要发现。
结论
通过 MR 分析发现了与 MAFLD 发展相关的新的因果代谢物，这表明未来有可能评估这些代谢物作为 MAFLD 预防或治疗的靶点。
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