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

• Published in: Frontiers in pharmacology Vol. 15; p. 1433519
• Main Authors: Ortega-Ayala, Adiel, De Andrés, Fernando, Llerena, Adrián, Bartolo-Montiel, Carlos Miguel, Acosta-Altamirano, Gustavo, Molina-Guarneros, Juan Arcadio
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30.09.2024
• Subjects: diabetes T2; HbA1c control; metformin; Pharmacology; rs622342; rs72552763; HbA1c control; diabetes T2; metformin; rs72552763; rs622342
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1433519

In Mexico, 75% of diabetes mellitus type 2 (DMT2) patients are not in glycaemic control criteria (HbA1c<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 , , and , 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. SNPs of (rs72552763, rs622342, rs12208357, rs2282143, rs594709, rs628031, and rs683369), (rs316019), and (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 <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. 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 (HRAEI) between October 2013 and December 2023. 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 ( = 0.036), metformin dose mg/kg/day ( = 0.003), plasmatic glucose mg/dL ( = 0.048), and HbA1c ( < 0.001). The median non-control survival rate was different across the 3 genotypes of rs62552763 in ( = 0.0034) and the dominant genotypic model GAT/GAT vs. GAT/del + del/del ( = 0.009). There were differences between rs622342 genotypes as well ( = 0.041). In GAT/GAT the Cox model found HR = 0.407 (IC95%: 0.202-0.818, = 0.011) in the univariate analysis and HR = 0.418 (IC95%: 0.204-0.856, = 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 , reported HR = 0.392 (IC95%: 0.169-0.910, = 0.029) in the multivariate analysis as well. 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 , will reach non-control in less time with respect to other patients. Therefore these genotypes may constitute a therapeutic response biomarker for this population.