Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients

Abstract

Metformin is an oral antidiabetic drug, commonly used for treating type 2 diabetes mellitus (T2DM) patients. It is transported into the hepatocytes by polyspecific organic cation transporter 1, which is encoded by the gene SLC22A1. It has been hypothesized that genetic variations of SLC22A1 gene will influence inter-individual variation in glucose lowering efficacy of metformin. Previous studies have demonstrated this in other populations with conflicting results, but it remains to be elucidated in Indian population. Henceforth, the objective of the study was to evaluate the impact of SLC22A1 rs622342 gene polymorphism on the clinical efficacy of metformin in South Indian T2DM patients. A total of 122 newly detected, treatment naive T2DM patients of either sex were included in this study. The patients were started on metformin monotherapy and followed up for 12 weeks. Genotype was determined using qRT-PCR. Before and after treatment with metformin, body mass index (BMI), serum lipid profile, glycated hemoglobin (HbA1c), fasting and postprandial glucose level, and blood pressure (BP) were measured. The study cohort mean age was 49.57 ± 9.88 years. Of the 122 T2DM patients, 93 were classified as responders and 29 as non-responders based on fall in HbA1c levels. Interestingly, carriers of one variant allele 'C' (AC) of rs622342 polymorphism were less among the responders than those who did not (44.8 vs. 22.6 %). The response was even lesser (13.8 vs. 4.3 %) in carriers of two copies of "C" allele (CC). On the contrary, patients with two copies of allele 'A' (AA) had 5.6 times greater chance of responding to metformin treatment. A similar trend was observed when the proportion was analyzed under different genetic models (OR 3.85, 95 % CI 1.61-9.19 for dominant; OR 3.56, 95 % CI 0.83-15.26 for recessive; OR 0.35, 95 % CI 0.14-0.86 for over-dominant; and OR 4.10, 95 % CI 1.78-9.43 for additive). Further, metformin showed significant beneficial effects on BMI, HbA1c, FPG, PPG, lipid parameters and BP. These data suggest that the allele and genotypes of SLC22A1 rs622342 gene polymorphism were associated with the therapeutic efficacy of metformin in South Indian patients with T2DM.

Altered Glycemic Control Associated With Polymorphisms in the SLC22A1 (OCT1) Gene in a Mexican Population With Type 2 Diabetes Mellitus Treated With Metformin: A Cohort Study

“…A significant increase in HbA 1c was observed in CC‐rs622342 ( β = 1.36; p < .001) T2D patients after 12 months with metformin treatment. Similar results were reported in South Indian T2D patients, where patients carrying the AA‐rs622342 genotype had 5.6 times better chance of response to metformin compared to patients carrying the CC genotype . For their part, Becker et al reported a significant association between individuals carrying the CC‐rs622342 genotype and an average increase of 0.02% in the HbA 1c levels.…”

“…Similar results were reported in South Indian T2D patients, where patients carrying the AA-rs622342 genotype had 5.6 times better chance of response to metformin compared to patients carrying the CC genotype. 19 For their part, Becker et al 9 reported a significant association between individuals carrying the CC-rs622342 genotype and an average increase of 0.02% in the HbA 1c levels. In addition, they identified a significant association between the interaction of the CC-rs622342 genotype and the A-rs2289669 allele (SLC47A1 gene), with the changes in HbA 1c levels in incident metformin users.…”

STK11 rs2075604 Polymorphism Is Associated with Metformin Efficacy in Chinese Type 2 Diabetes Mellitus

“…Metformin dosages ranged from 500 to 2000 mg per day among individuals and were adjusted according to the changes of glucose. Based on the response to metformin, these T2DM patients were divided into two groups, the response group (decrease in HbA1c levels was by more than 0.5% from the baseline) and nonresponse group (decrease in HbA1c levels was less than 0.5% from the baseline) [7, 8]. …”

“…On the other hand, about 10–20% of patients are not able to tolerate the side effects of metformin [5]. According to the former research, some genetic polymorphisms in genes encoding proteins, such as SLC22A1 [6, 7], OCT1 [8], and IL-1B [9], are responsible for the pharmacokinetics or pharmacodynamics of metformin. Recently, the AMPK pathway and its regulators are gaining the attention for the difference of the metformin effect.…”

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

“…In a European cohort study, the C allele was associated with greater HbA1c reduction in diabetic subjects treated with MET, but this interaction could not be replicated in other cohorts of similar ethnicity (American‐European population and Central European drug naïve T2DM patients) . Indeed, in a study carried out in 122 newly diagnosed, treatment naive T2DM patients from South India, carriers of the rs622342 C variant were found to be less responsive to MET action on HbA1c . In a small clinical trial on patients with castration‐resistant prostate cancer, homozygous carriers of the rs622342 C variant showed lower‐MET‐related toxicity and reduced drug efficacy on prostate cancer progression compared with A allele carriers .…”