Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russian Federation; Research Centre for Medical Genetics, 1 Moskvorechie St., Moscow 115522, Russian Federation.
Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russian Federation; Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russian Federation.
Gene. 2025 Jan 30;935:149050. doi: 10.1016/j.gene.2024.149050. Epub 2024 Nov 1.
Aminopeptidase N (ANPEP), a membrane-associated ectoenzyme, has been identified as a susceptibility gene for type 2 diabetes (T2D) by genome-wide association and transcriptome studies; however, the mechanisms by which this gene contributes to disease pathogenesis remain unclear. The aim of this study was to determine the comprehensive contribution of ANPEP polymorphisms to T2D risk and annotate the underlying mechanisms. A total of 3206 unrelated individuals including 1579 T2D patients and 1627 controls were recruited for the study. Twenty-three common functional single nucleotide polymorphisms (SNP) of ANPEP were genotyped by the MassArray-4 system. Six polymorphisms, rs11073891, rs12898828, rs12148357, rs9920421, rs7111, and rs25653, were found to be associated with type 2 diabetes (Pperm ≤ 0.05). Common haplotype rs9920421G-rs4932143G-rs7111T was strongly associated with increased risk of T2D (Pperm = 5.9 × 10-12), whereas two rare haplotypes such as rs9920421G-rs4932143C-rs7111T (Pperm = 6.5 × 10-40) and rs12442778A-rs12898828A-rs6496608T-rs11073891C (Pperm = 1.0 × 10-7) possessed strong protection against disease. We identified 38 and 109 diplotypes associated with T2D risk in males and females, respectively (FDR ≤ 0.05). ANPEP polymorphisms showed associations with plasma levels of fasting blood glucose, aspartate aminotransferase, total protein and glutathione (P < 0.05), and several haplotypes were strongly associated with the levels of reactive oxygen species and uric acid (P < 0.0001). A deep literature analysis has facilitated the formulation of a hypothesis proposing that increased plasma levels of ANPEP as well as liver enzymes such as aspartate aminotransferase, alanine aminotransferase and gammaglutamyltransferase serve as an adaptive response directed towards the restoration of glutathione deficiency in diabetics by stimulating the production of amino acid precursors for glutathione biosynthesis.
天冬氨酰肽酶 N（ANPEP）是一种膜相关的外切酶，已通过全基因组关联和转录组研究被鉴定为 2 型糖尿病（T2D）的易感基因；然而，该基因导致疾病发病机制的机制尚不清楚。本研究的目的是确定 ANPEP 多态性对 T2D 风险的综合贡献，并注释潜在机制。共纳入 3206 名无关个体，包括 1579 名 T2D 患者和 1627 名对照，用于研究。使用 MassArray-4 系统对 ANPEP 的 23 个常见功能单核苷酸多态性（SNP）进行基因分型。rs11073891、rs12898828、rs12148357、rs9920421、rs7111 和 rs25653 6 个多态性与 2 型糖尿病相关（Pperm≤0.05）。常见单倍型 rs9920421G-rs4932143G-rs7111T 与 T2D 风险增加强烈相关（Pperm=5.9×10-12），而两种罕见单倍型如 rs9920421G-rs4932143C-rs7111T（Pperm=6.5×10-40）和 rs12442778A-rs12898828A-rs6496608T-rs11073891C（Pperm=1.0×10-7）对疾病具有强烈的保护作用。我们在男性和女性中分别鉴定出 38 个和 109 个与 T2D 风险相关的二倍型（FDR≤0.05）。ANPEP 多态性与空腹血糖、天冬氨酸转氨酶、总蛋白和谷胱甘肽的水平相关（P<0.05），并且一些单倍型与活性氧和尿酸的水平强烈相关（P<0.0001）。深入的文献分析提出了一个假设，即 ANPEP 血浆水平以及天冬氨酸转氨酶、丙氨酸转氨酶和谷氨酰转移酶等肝脏酶的升高可能是一种适应性反应，通过刺激谷胱甘肽生物合成的氨基酸前体的产生，来恢复糖尿病患者的谷胱甘肽缺乏。
