Background:The treatment of epilepsy using antiepileptogenic drugs is complicated by drug resistance, resulting in treatment failure in more than one-third of cases. Human P-glycoprotein (hPGP;MDR1) is a known epileptogenic mediator.Methods:Given that experimental investigations have suggested a role for pharmacogenetics in this treatment failure, it would be of interest to study hPGP polymorphisms that might contribute to the emergence of drug resistance. Changes in protein functional activity could result from mutations as well as altered abundance. Bioinformatics approaches were used to assess and rank the functional impact of 20 missenseMDR1polymorphisms and the top five were selected. The structures of the wildtype and variant hPGP were modelled based on the mouse PGP structure. Docking studies of the wildtype and variant hPGP with four standard anti-epileptic drugs were carried out.Results:Our results revealed that the drug binding site with respect to the wildtype protein was uniform. However, the variant hPGP proteins displayed a repertoire of binding sites with stronger binding affinities towards the drug.Conclusion:Our studies indicated that specific polymorphisms inMDR1could drive conformational changes of PGP structure, facilitating altered contacts with drug-substrates and thus modifying their bioavailability. This suggests thatMDR1polymorphisms could actively contribute to the emergence of pharmaco-resistance in antiepileptic therapy.
Background
Diabetic nephropathy is known to be a leading complication of diabetes mellitus, characterized by diverse aspects such as high urinary albumin level, elevated blood pressure, and genetic susceptibility leading to end-stage renal disease. The current study was carried out to investigate the association of eNOS and TGFβ1 gene polymorphisms in the progression of diabetic nephropathy among type 2 diabetic patients in the South Indian population. The eNOS and TGFβ1 genetic variants were genotyped in 280 T2DM patients, 140 with DN, 140 without DN, and 140 controls. Genotyping was performed using ARMS PCR and the genomic variants were confirmed by the Sanger sequencing method.
Results
A significant (p < 0.05) association was observed in the genotypic frequencies of eNOS (G > T) polymorphism in the T2DM patients with diabetic nephropathy when compared to controls. The frequency of TT (heterozygous) genotype was observed to increase in patients with type 2 diabetes and DN when compared to the diabetic patients without DN and controls. This indicates that diabetic patients with TT genotype are at an increased risk to develop DN. However, TGFβ1 (G > C) polymorphism did not show any association in the allele and genotypic frequencies with DN when compared with T2DM and controls.
Conclusion
The results of the study propose a strong influence of TT genotype of eNOS gene be significantly linked with diabetic nephropathy in T2DM patients. Whereas no association was examined concerning TGFβ1 gene polymorphism and DN. Nevertheless, large sample size studies are required to confirm the part of these genetic variants in the development of DN.
Background
Very few studies have investigated the role of PTX3 and PVT1 genetic polymorphisms and their association in the progression of diabetic kidney diseases. Diabetic kidney disease (DKD) is a prominent reason of end-stage renal disease and also known to be involved in the high mortality rate of cardiovascular diseases. The current study has examined the role of PTX3 and PVT1 genetic polymorphisms in the development of diabetic kidney disease in type 2 diabetic patients.
Results
A significant difference between the genotypes and alleles of the rs2305619 polymorphism was observed in the diabetic patients with DKD when compared with the control group. The frequency of GG genotype was observed to be high in diabetic patients with DKD when compared to the other two groups. This specified that diabetic patients with GG genotype are at an increased risk to develop DKD. However, PVT1 (G/A) polymorphism did not show any association in the allele and genotypic frequencies with DKD when compared with T2DM and controls.
Conclusion
Our results propose a major influence of GG genotype of rs2305619 polymorphism to be significantly linked with an increased risk of DKD in type 2 diabetic patients.
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