Impact of SLC22A1 variants rs622342 and rs72552763 on HbA1c and metformin plasmatic concentration levels in patients with type 2 diabetes mellitus.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is a major global health problem. Response to first-line therapy is variable. This is partially due to interindividual variability across those genes codifying transport, metabolising, and drug activation proteins involved in first-line pharmacological treatment. Single nucleotide polymorphisms (SNPs) of genes SLC22A1, SLC22A2 and SLC22A3 affect metformin therapeutic response in patients with T2DM patients. The present study investigated allelic and genotypic frequencies of organic cation (OCT)1, OCT2, and OCT3 polymorphisms among metformin-treated patients with type 2 diabetes mellitus (T2DM). It also reports the association between clinical and genetic variables with glycated haemoglobin (HbA1c) control in 59 patients with T2DM. Patients were genotyped through real-time PCR (TaqMan assays). Metformin plasmatic levels were determined by mass spectrometry. Neither the analysis of HbA1c control by SNPs in SLC22A1, SLC22A2 and SLC22A3, nor the dominant genotypic model analysis yielded statistical significance between genotypes in polymorphisms rs72552763 (P=0.467), rs622342 (P=0.221), rs316019 (P=0.220) and rs2076828 (P=0.215). HbA1c levels were different in rs72552763 [GAT/GAT, 6.0 (5.7-6.6), GAT/del=6.5 (6.2-9.0), del/del=6.5 (6.4-6.8); P=0.022] and rs622342 [A/A=6.0 (5.8-6.5), A/C=6.4 (6.1-7.7), C/C=6.8 (6.4-9.3); P=0.009] genotypes. The dominant genotypic model found the lowest HbA1c levels in GAT/GAT (P=0.005) and A/A (P=0.010), in rs72552763 (GAT/GAT vs. GAT/del + del/del) and rs622342 (A/A vs. A/C + CC), respectively. There was a significant correlation between HbA1c levels and metformin dosage amongst del allele carriers in rs72552763 (ß1=0.14, P<0.001, r2=0.387), as opposed to GAT/GAT in rs72552763. There were no differences between HbA1c values in the test set and those predicted by machine learning models employing a simple linear regression based on metformin dosage. Therefore, rs72552763 and rs622342 polymorphisms in SLC22A1 may affect metformin response determined by HbA1c levels in patients with T2DM. The del allele of SNP rs72552763 may serve as a metformin response biomarker.