SLCO1B1 c.521T>C gene polymorphism decreases hypoglycemia risk in sulfonylurea-treated type 2 diabetic patients.

Q2 Pharmacology, Toxicology and Pharmaceutics

Drug metabolism and personalized therapy Pub Date : 2022-12-01 DOI:10.1515/dmpt-2022-0131

Georgia Ragia, Natalia Atzemian, Anthi Maslarinou, Vangelis G Manolopoulos

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引用次数: 2

Abstract

Objectives: Pharmacogenomics can explain some of the heterogeneity of sulfonylurea (SU)-related hypoglycemia risk. Recently, a role of OATP1B1, encoded by SLCO1B1 gene, on SU liver transport prior of metabolism has been uncovered. The aim of the present study was to explore the potential association of SLCO1B1 c.521T>C polymorphism, leading to reduced OATP1B1 function, with SU-related hypoglycemia risk.

Methods: Study cohort consists of 176 type 2 diabetes patients treated with the SUs glimepiride or gliclazide. 92 patients reported SU-related hypoglycemia, while 84 patients had never experienced a hypoglycemic event. Patients were previously genotyped for CYP2C9 *2 and *3 variant alleles that lead to decreased enzyme activity of the SU metabolizing enzyme CYP2C9 and have been associated with increased SU-related hypoglycemia risk. SLCO1B1 c.521T>C polymorphism was genotyped by use of PCR-RFLP analysis.

Results: SLCO1B1 c.521TC genotype frequency was significantly lower in hypoglycemic cases than non-hypoglycemic controls (15.2% vs. 32.1%, p=0.008). In an adjusted model, c.521TC genotype significantly reduced the risk of hypoglycemia (OR 0.371; 95% C.I. 0.167-0.822; p=0.015). In CYP2C9 intermediate metabolizers (n=54) c.521TC genotype frequency was significantly decreased in cases compared to controls (3 out of 36 cases, 8.3% vs. 7 out of 18 controls, 38.9%, p=0.012). A similar albeit not significant difference of SLCO1B1 c.521TC genotype was present in CYP2C9 extensive metabolizers (n=120) (18.2% in cases vs. 30.8% in controls, p=0.113).

Conclusions: We have found a protective effect of SLCO1B1 c.521C variant on SU-related hypoglycemia risk both independently and in interaction with CYP2C9 phenotypes. Our results suggest a possible linkage of SLCO1B1 c.521T>C polymorphism with variants in other genes impairing OATPs expressed in pancreatic islets that could interfere with SU tissue distribution.

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SLCO1B1 C . 521t >C基因多态性降低磺脲类药物治疗的2型糖尿病患者低血糖风险

目的:药物基因组学可以解释磺酰脲(SU)相关低血糖风险的一些异质性。近年来，研究人员发现由SLCO1B1基因编码的OATP1B1在SU代谢前肝脏转运中的作用。本研究的目的是探讨SLCO1B1 C . 521t >C多态性(导致OATP1B1功能降低)与糖尿病相关低血糖风险的潜在关联。方法:研究队列包括176例接受SUs格列美脲或格列齐特治疗的2型糖尿病患者。92例患者报告了与糖尿病相关的低血糖，84例患者从未发生过低血糖事件。患者先前对CYP2C9 *2和*3变异等位基因进行基因分型，这些等位基因导致SU代谢酶CYP2C9酶活性降低，并与SU相关低血糖风险增加相关。采用PCR-RFLP方法对SLCO1B1 C . 521t >C多态性进行基因分型。结果:低血糖组SLCO1B1 c.521TC基因型频率明显低于非低血糖组(15.2% vs. 32.1%， p=0.008)。在调整后的模型中，c.521TC基因型显著降低低血糖的风险(OR 0.371;95% c.i. 0.167-0.822;p = 0.015)。在CYP2C9中间代谢物(n=54)中，与对照组相比，c.521TC基因型频率显著降低(36例中有3例，8.3% vs. 18例对照中有7例，38.9%，p=0.012)。在CYP2C9广泛代谢者(n=120)中，SLCO1B1 c.521TC基因型也存在类似但不显著的差异(病例18.2% vs对照组30.8%，p=0.113)。结论:我们发现了SLCO1B1 c.521C变异对糖尿病相关低血糖风险的保护作用，无论是独立的还是与CYP2C9表型的相互作用。我们的研究结果表明，SLCO1B1 C . 521t >C多态性与其他基因的变异可能存在联系，这些基因会损害胰岛中表达的oats，从而干扰SU组织分布。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug metabolism and personalized therapy Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

2.30

自引率

0.00%

发文量

期刊介绍： Drug Metabolism and Personalized Therapy (DMPT) is a peer-reviewed journal, and is abstracted/indexed in relevant major Abstracting Services. It provides up-to-date research articles, reviews and opinion papers in the wide field of drug metabolism research, covering established, new and potential drugs, environmentally toxic chemicals, the mechanisms by which drugs may interact with each other and with biological systems, and the pharmacological and toxicological consequences of these interactions and drug metabolism and excretion. Topics: drug metabolizing enzymes, pharmacogenetics and pharmacogenomics, biochemical pharmacology, molecular pathology, clinical pharmacology, pharmacokinetics and drug-drug interactions, immunopharmacology, neuropsychopharmacology.