Impact of SLC22A1 and CYP2C9 Gene Variants on Glycemic Response to Metformin/Sulfonylurea Therapy in T2DM Patients in Port Harcourt, Nigeria

Aim: To evaluate the influence of some variants of SLC22A1 and CYP2C9 genes on glycaemic response in T2DM subjects on metformin/Sulphonylureas combination therapy in Port Harcourt.

Study Design: Cross-sectional Study.

Place and Duration of Study: Port-Harcourt, Nigeria, Inqaba Biotec (molecular analysis) and Evashalom Medical Diagnostic services, between November 2022 and April 2023.

Methodology: Ninety (90) subjects between aged between 18 - 70years among which 54 were females and 26 males were recruited. Individuals with diagnosed T2DM of at least 1 year, and on continuous metformin/sulphonylureas combination therapy for at least six (6) months prior to the study were selected for this study. Ten (10.0) ml of overnight fasting blood sample was obtained from each subject. This was after completing the questionnaire. Their body weight in kilogram, height in meter was also be measured and recorded. Eight SNPs, four each from SLC22A1 and CYP2C9 genes respectively were selected and genotyped using Mass Array. Blood glucose, total cholesterol (TCHOL), triglycerides (TG) and high-density lipoprotein (HDL-c) were measured by enzymatic colorimetric methods and low-density lipoprotein cholesterol (LDL-c), HOMA_IR, HOMA-β were calculated for each sample. Statistical Analysis was carried out using GraphPad Prism 9.03. Statistical comparisons of the means between groups were made using t-test and oneway analysis of variance (ANOVA). Genotypic and allelic distribution employed the Hardy-Weinberg equilibrium test (HWE). The minor allele frequency (MAF) was calculated using Excel. Furthermore, the associations between the alleles of SNPs and glycaemic response response were assessed using the chi-square test and 95% confidence intervals. Statistical significance was set at p < 0.05.

Results: This study showed that the AA genotype of rs622342 (SLC22A1) was significantly associated (p=0.003) with controlled T2DM in response to metformin/sulphonylureas combination therapy. The results in uncontrolled T2DM showed an association between variants of rs594709(AG/GG) with reduced level of HOMA-IR (p<0.0331), rs622342 (CA/AA) with reduced level of HOMA-IR (p<0.0313), and rs 9332214 variant (TT) with reduced level of AIP (p<0.0245). Moreover, in Obese, the variants of rs594709(AG/GG) was found to be associated with a reduced level of TCHOL(p<0.0054), rs622342 (CA/AA) with a reduced level of Lipo A (p=0.0400), and rs 9332214 (TC/CC) with a reduced level of HbAIc (p<0.0265).On the other hand, in hypertensives, an association was found between the variant rs622342 (CA/AA) with a reduced level of BMI (p=0.0416).

Conclusion: Individuals with the AA genotype of rs622342 are likely to have a better glycaemic response as compared to those carrying the AC/CC genotype receiving metformin/sulphonylurea combination therapy.