AUTHOR=Ortega-Ayala Adiel , De Andrés Fernando , Llerena Adrián , Bartolo-Montiel Carlos Miguel , Acosta-Altamirano Gustavo , Molina-Guarneros Juan Arcadio 

TITLE=Longitudinal assessment of SNPs rs72552763 and rs622342 in SLC22A1 over HbA1c control among Mexican-Mestizo diabetic type 2 patients

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1433519

DOI=10.3389/fphar.2024.1433519

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> In Mexico, 75% of diabetes mellitus type 2 (DMT2) patients are not in glycaemic control criteria (HbA1c&lt;7%); this entails a significantly variable drug response. Amongst the factors influencing such variability, are genetics, more specifically, single nucleotide polymorphisms (SNPs). Three genes implied in metformin pharmacokinetics are <italic>SLC22A1</italic>, <italic>SLC22A2</italic>, and <italic>SLC22A3</italic>, which are polymorphic. While there have been cross-sectional studies on their SNPs impact over drug response, a longitudinal study would contribute valuable information on their effect over time.</p><p><bold>Methods:</bold> SNPs of <italic>SLC22A1</italic> (rs72552763, rs622342, rs12208357, rs2282143, rs594709, rs628031, and rs683369), <italic>SLC22A2</italic> (rs316019), and <italic>SLC22A3</italic> (rs2076828), were determined through PCR-TR. The clinical records of 69 patients undergoing metformin monotherapy were retrospectively assessed. Metformin is the first line treatment against DMT2. A level of HbA1c &lt;7% (time 0) was considered as an inescapable inclusion criterion. The study’s cases were those patients who reported HbA1c ≥ 7% (time1) after time 0 (t0). Kaplan-Meier curves including a Log-Rank test and a Cox multivariate analysis of proportional risks were performed.</p><p><bold>Aim:</bold> Determining clinical, biochemical, and genetic variables which may affect non-control (HbA1c ≥ 7%) survival time spans amongst DMT2 Mexican-Mestizo patients undergoing metformin monotherapy at <italic>Hospital Regional de Alta Especialidad de Ixtapaluca</italic> (HRAEI) between October 2013 and December 2023.</p><p><bold>Results:</bold> All 69 patients were monitored over a median period of 642 days (273-1,134). A comparison between time 0 and time 1 (t1) revealed differences in weight (<italic>p</italic> = 0.036), metformin dose mg/kg/day (<italic>p</italic> = 0.003), plasmatic glucose mg/dL (<italic>p</italic> = 0.048), and HbA1c (<italic>p</italic> &lt; 0.001). The median non-control survival rate was different across the 3 genotypes of rs62552763 in <italic>SLC22A1</italic> (<italic>p</italic> = 0.0034) and the dominant genotypic model GAT/GAT vs. GAT/del + del/del (<italic>p</italic> = 0.009). There were differences between rs622342 genotypes as well (<italic>p</italic> = 0.041). In GAT/GAT the Cox model found HR = 0.407 (IC95%: 0.202–0.818, <italic>p</italic> = 0.011) in the univariate analysis and HR = 0.418 (IC95%: 0.204–0.856, <italic>p</italic> = 0.034) in the multivariate analysis, adjusted by initial metformin dose (mg/kg/day), initial weight (kg), and final metformin dose (mg/kg/day). Genotype A/A of rs622342 in <italic>SLC22A1</italic>, reported HR = 0.392 (IC95%: 0.169–0.910, <italic>p</italic> = 0.029) in the multivariate analysis as well.</p><p><bold>Conclusion:</bold> Among DMT2 Mexican-Mestizo patients undergoing metformin monotherapy the minor allele del in rs72552763 and the minor allele C in rs622342 reported a significantly shorter survival median respect to the wild type variant. Patients carrying del in rs72552763 or C in rs622342, both in <italic>SLC22A1</italic>, will reach non-control in less time with respect to other patients. Therefore these genotypes may constitute a therapeutic response biomarker for this population.</p>