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墨西哥人群中三种二甲双胍转运体多态性的等位基因频率和基因型分布及其在2型糖尿病药物基因组学中的应用。

Allele frequencies and genotype distribution of three metformin transporter polymorphisms in Mexican population and their application in pharmacogenomics of type 2 diabetes.

作者信息

Chávez-Arreola Oscar I, Lazalde Brissia, López-López Marisol, Ortega-Vázquez Alberto, Torres-Salazar Quitzia L

机构信息

Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico.

Juarez University of the State of Durango, Durango, Mexico.

出版信息

Front Pharmacol. 2024 Nov 1;15:1466394. doi: 10.3389/fphar.2024.1466394. eCollection 2024.

DOI:10.3389/fphar.2024.1466394
PMID:39555090
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11565514/
Abstract

BACKGROUND

Metformin is the first-line antidiabetic therapy for type 2 diabetes in Mexico, despite recent recommendations highlighting alternatives like GLP-1 receptor agonists for individuals with obesity. Metformin elimination is reliant on liver and kidney function, and variants in transport proteins such as Multidrug and Toxin Extrusion Protein 1 (MATE1), MATE2, and Organic Cation Transporter 2 (OCT2) can influence its pharmacokinetics. Understanding these variants' frequencies in the Mexican population is crucial for tailoring personalized treatment strategies.

OBJECTIVE

This study aimed to determine the genotypic and allelic frequencies of key variants in metformin transporters within a Mexican population, addressing the interindividual variability in drug response.

METHODOLOGY

Genetic analysis was conducted on 101 healthy, unrelated Mexican subjects who were genotyped for the MATE1, MATE2, and OCT2 variants using allele-specific real-time PCR assays.

RESULTS

The allele frequencies were 0.07 for OCT2, 0.23 for MATE1, and 0.67 for MATE2. The g.-66T→C variant was found only in wild-type and heterozygous forms. Comparative analysis indicated significant differences in allele frequencies between this Mexican population and other ethnic groups, highlighting potential implications for metformin efficacy and safety.

CONCLUSION

This study provides crucial insights into the genetic variability of metformin transporter genes in a Mexican population, offering a foundation for personalized therapeutic approaches in type 2 diabetes management.

摘要

背景

在墨西哥,二甲双胍是2型糖尿病的一线抗糖尿病治疗药物,尽管最近的建议强调对于肥胖个体可选用如胰高血糖素样肽-1(GLP-1)受体激动剂等替代药物。二甲双胍的消除依赖于肝脏和肾脏功能,而转运蛋白如多药和毒素外排蛋白1(MATE1)、MATE2以及有机阳离子转运体2(OCT2)中的变异可影响其药代动力学。了解这些变异在墨西哥人群中的频率对于制定个性化治疗策略至关重要。

目的

本研究旨在确定墨西哥人群中二甲双胍转运体关键变异的基因型和等位基因频率,以解决药物反应的个体间差异问题。

方法

对101名健康、无亲缘关系的墨西哥受试者进行基因分析,使用等位基因特异性实时PCR检测法对MATE1、MATE2和OCT2变异进行基因分型。

结果

OCT2的等位基因频率为0.07,MATE1为0.23,MATE2为0.67。g.-66T→C变异仅在野生型和杂合子形式中发现。比较分析表明,该墨西哥人群与其他种族群体的等位基因频率存在显著差异,这突出了对二甲双胍疗效和安全性的潜在影响。

结论

本研究为墨西哥人群中二甲双胍转运体基因的遗传变异性提供了重要见解,为2型糖尿病管理中的个性化治疗方法奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9a/11565514/9c6b50c9ef73/fphar-15-1466394-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9a/11565514/9c6b50c9ef73/fphar-15-1466394-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9a/11565514/9c6b50c9ef73/fphar-15-1466394-g001.jpg

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本文引用的文献

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Introduction and Methodology: Standards of Care in Diabetes-2024.引言与方法:2024年糖尿病护理标准
Diabetes Care. 2024 Jan 1;47(Supplement_1):S1-S4. doi: 10.2337/dc24-SINT.
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Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP).在糖尿病预防计划(DPP)中的一个多祖系全基因组关联研究中,鉴定影响二甲双胍反应的遗传变异。
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The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.新型 MATE1 和 MATE2 启动子变异对二甲双胍药代动力学和药效学的影响。
Clin Pharmacol Ther. 2013 Feb;93(2):186-94. doi: 10.1038/clpt.2012.210. Epub 2012 Oct 17.
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The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c.二甲双胍的药物遗传学及其对血浆二甲双胍稳态水平和糖化血红蛋白 A1c 的影响。
Pharmacogenet Genomics. 2011 Dec;21(12):837-50. doi: 10.1097/FPC.0b013e32834c0010.
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A common 5'-UTR variant in MATE2-K is associated with poor response to metformin.MATE2-K 中的常见 5'-UTR 变异与二甲双胍治疗反应不佳相关。
Clin Pharmacol Ther. 2011 Nov;90(5):674-84. doi: 10.1038/clpt.2011.165. Epub 2011 Sep 28.
7
Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations.表达人 OCT1/MATE1 或 OCT2/MATE1 的双转染 MDCK 细胞:有机阳离子摄取和细胞间转运的决定因素。
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