Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients

Zaharenko, Linda; Kalniņa, Ineta; Geldnere, Kristine; Konrāde, Ilze; Grı̄nberga, Solveiga; Židzik, Jozef; Javorský, Martin; Lejnieks, Aivars; Ņikitina-Zaķe, Liene; Fridmanis, Dāvids; Pečulis, Raitis; Radoviča-Spalviņa, Ilze; Hartmane, Dace; Pugovičs, Osvalds; Tkáč, Ivan; Klimčáková, Lucia; Pīrāgs, Valdis; Kloviņš, Jānis

doi:10.1530/eje-16-0347

Cited by 24 publications

(12 citation statements)

References 38 publications

(48 reference statements)

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“…The intergenic variants rs3119309, rs7757336 and rs2481030, located between SLC22A2 and SLC22A3 were significantly associated with metformin inefficiency in European cohort. Found in this study polymorphisms were noncoding but they could be in linkage disequilibrium with any causal SNPs within coding/regulatory regions of SLC22A2, SLC22A3 or even SLC22A1 , resulting in altered transport activity or expression level in target tissues [ 35 ]. However, in an unselected sample of 103 healthy male Caucasian volunteers no significant association between renal metformin clearance and some variants of SLC22A2 (rs10755577, rs17588242, Val502 , rs315996, rs316019, rs17589858, Thr130 , rs2928035, rs316024, rs316025, rs316026, rs3127573, rs533452 and rs662301) was determined [ 57 ].…”

Section: Genes Associated With Metformin Responsementioning

confidence: 99%

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Nasykhova

Tonyan

Михайлова

et al. 2020

IJMS

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Type 2 diabetes mellitus (T2D) is a chronic metabolic disease resulting from insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction. The incidence of type 2 diabetes mellitus is increasing worldwide and nowadays T2D already became a global epidemic. The well-known interindividual variability of T2D drug actions such as biguanides, sulfonylureas/meglitinides, DPP-4 inhibitors/GLP1R agonists and SGLT-2 inhibitors may be caused, among other things, by genetic factors. Pharmacogenetic findings may aid in identifying new drug targets and obtaining in-depth knowledge of the causes of disease and its physiological processes, thereby, providing an opportunity to elaborate an algorithm for tailor or precision treatment. The aim of this article is to summarize recent progress and discoveries for T2D pharmacogenetics and to discuss the factors which limit the furthering accumulation of genetic variability knowledge in patient response to therapy that will allow improvement the personalized treatment of T2D.

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Section: Genes Associated With Metformin Responsementioning

confidence: 99%

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Nasykhova

Tonyan

Михайлова

et al. 2020

IJMS

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“…As far as we know to date, there are 11 studies on functional and phenotypic alterations suspected to be related to human OCT-3 polymorphisms [28,29,30,31,32,33,34,35,36,37]. Yamauchi et al reported that four major genetic polymorphisms (S116A, R120R, I140T, and A411A) of the OCT-3 gene including synonymous alterations were investigated concerning the relationship between the allele frequency and asthma severities, and were classified into two groups (mild and moderate/severe) on the basis of the Japanese asthma severity guidelines.…”

Section: Histamine Transport In the Pathophysiology Of Asthmamentioning

confidence: 99%

The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy

Yamauchi¹,

Ogasawara

2019

IJMS

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Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous clinical trials of H1 receptor antagonists (H1RAs) as a treatment for asthma were not successful. In recent years, type 2 innate immunity has been demonstrated to be involved in allergic airway inflammation. Allergic asthma is defined by IgE antibody-mediated mast cell degranulation, while group 2 innate lymphoid cells (ILC2) induce eosinophilic inflammation in nonallergic asthma without allergen-specific IgE. Anti-IgE therapy has demonstrated prominent efficacy in the treatment of severe allergic asthmatics sensitized with specific perennial allergens. Furthermore, recent trials of specific cytokine antagonists indicated that these antagonists were effective in only some subtypes of asthma. Accordingly, H1RAs may show significant clinical efficacy for some subtypes of allergic asthma in which histamine is deeply associated with the pathophysiology.

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“…Analysis of pharmacodynamic data in 57 healthy volunteers with mixed ethnicities (majority African American, n = 33; Asian, n = 18; Caucasian, n = 6) showed that the variant rs2076828 was associated with reduced response to metformin during an oral glucose tolerance test [77]. Furthermore, a study in 233 newly diagnosed Caucasian T2DM patients showed that minor alleles of rs2481030 located in the intergenic region between SLC22A2 and SLC22A3 are associated with metformin inefficiency [78]. However, another study in 103 healthy male Caucasians reported no significant effect of several SLC22A3 variants in the disposition to metformin [20].…”

Section: Genetic Polymorphisms In the Oct3 Gene (Slc22a3)mentioning

confidence: 99%

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

Zazuli

Duin

Jansen

et al. 2020

IJMS

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A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.

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Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients

Cited by 24 publications

References 38 publications

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

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