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 for the first time (Pperm<0.05). Common haplotype rs9920421G-rs4932143G-rs7111T was strongly associated with increased risk of T2D (Pperm=5.9x10-12), whereas two rare haplotypes such as rs9920421G-rs4932143C-rs7111T (Pperm=6.5x10-40) and rs12442778A-rs12898828A-rs6496608T-rs11073891C (Pperm=1.0x10-7) 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 gamma-glutamyltransferase 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.

中文翻译：

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ANPEP 基因与 2 型糖尿病之间的联系可能是通过谷胱甘肽代谢和氧化还原稳态的破坏介导的

氨肽酶 N (ANPEP) 是一种膜相关胞外酶，通过全基因组关联和转录组研究已被确定为 2 型糖尿病 (T2D) 的易感基因；然而，该基因促进疾病发病机制的机制仍不清楚。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其潜在机制。该研究共招募了 3206 名无关个体，其中包括 1579 名 T2D 患者和 1627 名对照者。通过 MassArray-4 系统对 ANPEP 的 23 个常见功能性单核苷酸多态性 (SNP) 进行了基因分型。首次发现rs11073891、rs12898828、rs12148357、rs9920421、rs7111和rs25653这6个多态性与2型糖尿病相关（Pperm<0.05）。常见的单倍型 rs9920421G-rs4932143G-rs7111T 与 T2D 风险增加密切相关 (Pperm=5.9x10-12)，而两种罕见的单倍型如 rs9920421G-rs4932143C-rs7111T (Pperm=6.5x10-40) 和 rs12442778A-rs 12898828A-rs6496608T- rs11073891C (Pperm=1.0x10-7) 具有很强的抗病保护作用。我们分别鉴定了 38 种和 109 种与男性和女性 T2D 风险相关的双倍型 (FDR<0.05)。ANPEP多态性显示与空腹血糖、天冬氨酸转氨酶、总蛋白和谷胱甘肽的血浆水平相关（P<0.05），并且一些单倍型与活性氧和尿酸水平密切相关（P<0.0001）。深入的文献分析促进了一个假设的形成，该假设提出，血浆 ANPEP 水平以及肝酶（如天冬氨酸转氨酶、丙氨酸转氨酶和 γ-谷氨酰转移酶）水平的增加是一种适应性反应，通过刺激糖尿病患者恢复谷胱甘肽缺乏症。生产用于谷胱甘肽生物合成的氨基酸前体。