Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes

Abstract

Pharmacogenetic studies revealed that variants in genes related to the pharmacokinetics of metformin were associated with glucose-lowering effect of metformin. The aim of this study was to investigate possible associations of the variants in genes encoding organic cationic transporters-solute carrier family 22, members A1, A2 (SLC22A1, SLC22A2) and solute carrier family 47, member A1 (SLC47A1) with response to metformin in type 2 diabetes. One hundred forty-eight drug-naive patients with type 2 diabetes were included in the study. Genotyping for SLC22A1 rs622342, SLC22A2 rs316019 and SLC47A1 rs2289669 variants was performed using real-time PCR with subsequent melting-curve analysis. SLC47A1 rs2289669 genotype was significantly associated with the reduction in haemoglobin A1c (HbA1c) after 6 months. Twenty percentage of patients with diabetes that are homozygous for A-allele of SLC47A1 had twofold reduction in HbA1c in comparison with the patients carrying G-allele (GG + GA: 0.55 ± 0.09% vs. AA: 1.10 ± 0.18%, p = 0.018). In conclusion, the results of this study might have in future practical implication in personalised treatment of patients with type 2 diabetes.

An Update on the Pharmacogenomics of Metformin: Progress, Problems and Potential

“…There was no association of the variant rs622342 identified by the Rotterdam study with either metformin level or HbA1c response [36]. Tkáč et al , attempting to replicate the Rotterdam study findings, also genotyped rs622342 in a prospective study of 148 drug-naive T2D patients started on metformin therapy; as with the Christensen study, there was no association with rs622342 and change in HbA1c after 6 months of therapy [38]. …”

“…In the Danish T2D intervention trial analyzed by Christensen et al described above, A270S did not show association with either metformin levels or change in HbA1c [36]. Tkáč et al , in their prospective study of 148 drug-naive T2D patients treated with metformin, similarly did not find an association with A270S and change in HbA1c after 6 months of therapy [38]. In the DPP, Jablonski et al genotyped A270S along with 43 OCT2 tagging SNPs and did not find association of any with the effectiveness of metformin to delay diabetes onset [40].…”

“…Similarly, Tkáč et al . observed a greater reduction in HbA1c in homozygous risk allele carriers [38]. In the DPP, the intronic SNP rs8065082, which is in LD with rs2289669 (r 2 = 0.8), was associated with the protective effect of metformin, with the minor allele associated with lower diabetes incidence in the metformin arm but not in the placebo cohort.…”

Polymorphisms of the KCNQ1 gene are associated with the therapeutic responses of sulfonylureas in Chinese patients with type 2 diabetes

“…Nevertheless, all patients were provided the same diabetes education according to guidelines on diet and exercise. And in the view of ethics, drug intervention as soon as possible to target blood glucose will benefit glycemic control as well as delay the occurrence of diabetic complications, lacking of placebo group in pharmacogenomics research focusing on well established anti-diabetic drug is reasonable and in accordance with study design performed by international counterparts [3,8,[40][41][42][43][44][45][46][47] . Fourth, the glucose metabolic parameters like HbA1c, insulin sensitivity and islet β-cell function during the 16-week treatment were not measured, which might further strengthen our findings.…”

Pharmacogenetics of hypoglycemic agents

“…Результаты исследования пока-зали более значимое снижение уровня HbA 1c у пациен-тов, гомозиготных по А-аллелю гена SLC47A1rs2289669, в сравнении с носителями G-аллеля данного гена (p=0,059). Пациенты, гомозиготные по А-аллелю гена SLC47A1rs2289669, составили 20% от всех обследованных и имели, таким образом, почти в 2 раза большее сниже-ние НbА1с, чем остальные [11].…”