Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
Nutrients. 2020 Dec 19;12(12):3890. doi: 10.3390/nu12123890.
Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine/methionine ratio with type 2 diabetes (OR = 0.87 (0.81-0.93)). Multivariable Mendelian randomization revealed inverse association for higher log-transformed tyrosine levels with type 2 diabetes (OR = 0.19 (0.04-0.88)), independent of other amino acids. Tyrosine might be a causal trait for type 2 diabetes independent of other diabetes-associated amino acids.
循环支链氨基酸、甘氨酸或芳香族氨基酸水平与 2 型糖尿病风险相关。然而，这些关联是否反映了因果关系，或者是否是由疾病早期发展过程驱动的，尚不清楚。我们根据代谢网络结构选择了与糖尿病相关的氨基酸比值，并在两项两样本孟德尔随机化研究中调查了这些比值和单个氨基酸对 2 型糖尿病风险的因果影响。氨基酸特征的遗传工具选择依赖于欧洲癌症前瞻性调查和营养研究（EPIC-Potsdam 研究）中代表性亚队列（多达 2265 名参与者）的全基因组关联研究以及来自全基因组关联研究的公共数据单氨基酸。对于选定的工具，结局关联来自 DIAGRAM（糖尿病遗传学复制和荟萃分析，74124 例病例和 824006 例对照）联盟。孟德尔随机化结果表明，ln 转化酪氨酸/蛋氨酸比值每增加一个标准差，2 型糖尿病的风险降低（OR=0.87（0.81-0.93））。多变量孟德尔随机化显示，较高的 log 转化酪氨酸水平与 2 型糖尿病呈负相关（OR=0.19（0.04-0.88）），与其他氨基酸无关。酪氨酸可能是 2 型糖尿病的一个独立于其他糖尿病相关氨基酸的因果特征。
