Abstract: Background: Inter-individual variation in response to metformin, which has been considered as a first line therapy for T2DM treatment is considerable. In the current study, it was aimed to investigate the impact of two genetic variants Leu125Phe (rs77474263) and Gly64Asp (rs77630697) in gene SLC47A1 on the clinical efficacy of metformin in T2DM Pakistani patients. Methods: The study included 800 T2DM patients (400 metformin responders and 400 metformin non-responders) along with 400 ethnically matched healthy individuals. The genotypes were determined by allele-specific polymerase chain reaction. In-silico analysis was done to confirm the effect of the two SNPs on the structure of genes. Association was statistically determined using SPSS software. Results: Minor allele frequency for rs77474263 and rs77630697 was 0.13 and 0.12. For SLC47A1 rs77474263 the homozygotes of one mutant allele ‘T’ (CT) of rs77474263 variant were fewer in metformin responders than metformin non-responders (29.2% vs. 35.5 %). Likewise, the efficacy was further reduced (7.2% vs. 4.0 %) in homozygotes of two copies of ‘T’ allele (TT). Remarkably, T2DM cases with two copies of allele ‘C’ (CC) had 2.11 times more probability to respond towards metformin monotherapy. For SLC47A1 rs77630697 the homozygotes of one mutant allele ‘A’ (GA) of rs77630697 variant were fewer in metformin responders than metformin non-responders (33.5% vs. 43.0 %). Likewise, the efficacy was further reduced (8.5% vs. 4.5%) in homozygotes of two copies of ‘A’ allele (AA). Remarkably, T2DM cases with two copies of allele ‘G’ (GG) had 2.41 times more probability to respond towards metformin monotherapy. In-silico analysis revealed that these two variants affect the structure and stability of their corresponding proteins. Conclusion: The present data suggest that SLC47A1 Leu125Phe (rs77474263) and Gly64Asp (rs77630697) polymorphisms were associated with the therapeutic response of metformin in T2DM patients of Pakistan.
Abstract: Matrix metalloproteinase-3 (MMP3) is key member
of the MMP family, and is known to be present in coronary
atherosclerotic. Several studies have demonstrated that MMP-3
5A/6A polymorphism modify each transcriptional activity in allele
specific manner. We hypothesized that this polymorphism may play
a role as risk factor for development of coronary stenosis. The aim of
our study was to estimate MMP-3 (5A/6A) gene polymorphism on
interindividual variability in risk for coronary stenosis in an Iranian
population.DNA was extracted from white blood cells and genotypes
were obtained from coronary stenosis cases (n=95) and controls
(n=100) by PCR (polymerase chain reaction) and restriction
fragment length polymorphism techniques. Significant differences
between cases and controls were observed for MMP3 genotype
frequencies (X2=199.305, p< 0.001); the 6A allele was less
frequently seen in the control group, compared to the disease group
(85.79 vs. 78%, 6A/6A+5A/6A vs. 5A/5A, P≤0.001). These data
imply the involvement of -1612 5A/6A polymorphism in coronary
stenosis, and suggest that probably the 6A/6A MMP-3 genotype is a
genetic susceptibility factor for coronary stenosis.