0
selected
-
1.
Investigation of ABCA1 C69T polymorphism in patients with type 2 diabetes mellitus.
Ergen, HA, Zeybek, U, Gök, O, Karaali, ZE
Biochemia medica. 2012;(1):114-20
Abstract
INTRODUCTION Non insulin dependent diabetes mellitus is the most common type of diabetes. Genetic factors, lipid profiles, hypertension are potential risk factors for diabetes mellitus. Adenosine binding cassette transporter proteins 1 (ABCA1) plays a role in cholesterol metabolism, especially high density lipoprotein (HDL-cholesterol). There are multiple mechanisms by which HDL-cholesterol can be atheroprotective, it is clear that the relative activity of ABCA1 plays a major role. We aimed to investigate association of ABCA1 C69T gene polymorphism with lipid levels in Turkish type 2 diabetic patients. MATERIALS AND METHODS After isolation of DNA by ethanol precipitation we determined ABCA1 gene polymorphism by using polimerase chain reaction--restriction fragment lenght polymorphism (PCR-RFLP) method in 107 type 2 diabetic patients and 50 healthy controls. RESULTS We have observed that the frequency of TT genotype is significantly higher in healthy controls compared to patients (14% vs. 3%; P = 0.008). Also frequency of T allele was higher in controls than in patients (34% vs. 21%; P = 0.020; OR (95% CI) = 0.52 (0.30-0.88)). There was no association of lipid levels and ABCA1 C69T polymorphism subgroups. CONCLUSION We have found significantly higher frequency of both T allele and genotype in control group when compared to patients that made us think that T allele may be a protective factor against diabetes mellitus. But, we could not find a relationship between genotypes and lipid concentrations in our two groups. Larger studies will help us to understand the relationship between ABCA1 C69T genotype and lipid parameters in diabetes mellitus.
-
2.
Non-neutral nonsynonymous single nucleotide polymorphisms in human ABC transporters: the first comparison of six prediction methods.
Hao, da C, Feng, Y, Xiao, R, Xiao, PG
Pharmacological reports : PR. 2011;(4):924-34
-
-
Free full text
-
Abstract
Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptibility to disease and altered drug/xenobiotic response. Abundant nsSNPs have been found in genes coding for human ATP-binding cassette (ABC) transporters, but there is little known about the relationship between the genotype and phenotype of nsSNPs in these membrane proteins. In addition, it is unknown which prediction method is better suited for the prediction of non-neutral nsSNPs of ABC transporters. We have identified 2,172 validated nsSNPs in 49 human ABC transporter genes from the Ensembl genome database and the NCBI SNP database. Using six different algorithms, 41 to 52% of nsSNPs in ABC transporter genes were predicted to have functional impacts on protein function. Predictions largely agreed with the available experimental annotations. Overall, 78.5% of non-neutral nsSNPs were predicted correctly as damaging by SNAP, which together with SIFT and PolyPhen, was superior to the prediction methods Pmut, PhD-SNP, and Panther. This study also identified any amino acids that were likely to be functionally critical but have not yet been studied experimentally. There was significant concordance between the predicted results of SIFT and PolyPhen. Evolutionarily non-neutral (destabilizing) amino acid substitutions are predicted to be the basis for the pathogenic alteration of ABC transporter activity that is associated with disease susceptibility and altered drug/xenobiotic response.
-
3.
ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin.
Tomlinson, B, Hu, M, Lee, VW, Lui, SS, Chu, TT, Poon, EW, Ko, GT, Baum, L, Tam, LS, Li, EK
Clinical pharmacology and therapeutics. 2010;(5):558-62
Abstract
The ATP-binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL-C level, in a gene-dose-dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL-C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.
-
4.
Investigation of ABCA1 C69T and G-191C polymorphisms in coronary artery disease.
Ergen, A, Isbir, S, Tekeli, A, Isbir, T
In vivo (Athens, Greece). 2008;(2):187-90
Abstract
BACKGROUND Defects of lipoprotein metabolism are common risk factors for coronary artery disease. The ATP binding cassette transporter 1 (ABCA1) plays an important role in carrying cholesterol from peripheral tissues to the liver. The role of ABCA1 C69T and G-191C gene polymorphisms on plasma lipid levels of patients with coronary artery disease was investigated. PATIENTS AND METHODS Seventy-seven patients with coronary artery disease and fifty healthy controls were studied. Gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS No differences in the distribution of C69T and G-191C polymorphisms were observed in the study groups. Plasma triacylglycerol and VLDL-cholesterol levels were shown to be higher in the patient group with the C69T CC genotype compared to these patients with the CT genotype. The C69T polymorphism was associated with HDL-cholesterol levels, which insignificantly increased in the order of the CC>CT>TT genotypes in our study. No association was found between G-191C genotype and lipid levels. CONCLUSION The results of our study suggested that polymorphisms of ABCA1 C69T polymorphism may be associated with plasma triacylglycerol and VLDL-cholesterol levels in coronary artery patients.
-
5.
An enhanced expression of ABC 1 transporter in circulating leukocytes as a potential molecular marker for the diagnostics of glaucoma.
Yeghiazaryan, K, Flammer, J, Wunderlich, K, Schild, HH, Orgul, S, Golubnitschaja, O
Amino acids. 2005;(2):207-11
Abstract
OBJECTIVE Glaucoma is a neurodegenerative disease. Since vascular dysregulation is supposed to be a risk factor for the development of glaucomatous damage, the preventive treatment might slow down the disease development. The efficiency of the therapeutic treatment depends particularly on a drug efflux pump regulated by ABC transporters. ABC 1 is also known to participate on the vascular regulation. This study was focused on the comparative analysis of ABC 1 expression levels in circulating leukocytes of non-glaucomatous individuals and glaucoma patients. RESULTS AND CONCLUSIONS The expression rates of ABC 1 were significantly increased in leukocytes of glaucoma patients compared to non-glaucomatous individuals. The expression level of ABC 1 was, furthermore, highly homogeneous in glaucoma patients. In contrast, these expression levels in non-glaucomatous individuals were extremely heterogeneous. This transporter acts as the energy-dependent unidirectional transmembrane cholesterol efflux pump and can export a wide range of hydrophobic drugs. Additionally an observed enhanced ABC 1 expression in circulating leukocytes may be implicated in the vascular regulation mechanisms of glaucoma. We proposed the enhanced expression of ABC 1 in leukocytes as a potential marker for the diagnostics and ex vivo molecular monitoring of glaucoma.
-
6.
Expression of ABC-1 transporter is elevated in human glioma cells under irradiation and temozolomide treatment.
Trog, D, Moenkemann, H, Haertel, N, Schüller, H, Golubnitschaja, O
Amino acids. 2005;(2):213-9
Abstract
OBJECTIVE Chemo-therapeutic treatment of glioma patients has minor success. Little is known about mechanisms of a pronounced resistance of gliomas towards actual therapies, yet. ABC-1 belongs to the group of transporters known to be involved in the export of hydrophobic substances and vascular regulation. This study investigates an effect of both temozolomide (TMZ) treatment and/or irradiation on the expression of the ABC-1 transporter in human U87-MG glioma cells. MATERIAL AND METHODS In parallel experiments U87-MG cells underwent either irradiation (RT), chemo-treatment (CT) using TMZ, and combined chemo/radiation-treatment (CT/RT). After each treatment the cells were incubated either 2 or 24 hours at 37 degrees C and counted before protein analysis using Western-Blot technique. RESULTS AND CONCLUSIONS An exponential growth of cellular density was observed for both untreated and irradiated cells being, however, about 2-times slower in irradiated compared to untreated cells. In contrast the density increase of chemo-treated cells as well as that of cells, which underwent the combined CT/RT treatment was of linear nature. ABC-1 expression was detected in untreated as well as treated cells. Increasing cell density and all kinds of treatment resulted in a considerably enhanced ABC-1 expression. CT treatment resulted in highly up-regulated ABC-1 expression especially in non-confluent cultures compared to untreated cells. Irradiation had a comparable or even higher inducible effect on the ABC-1 expression rates depending, however, on cell density. The highest expression rates were observed in cultures with high cellular density 2 hours after application of the combined treatment. Strong up-regulation of ABC-1 expression under both irradiation and chemo-treatment might be a clue to multidrug and irradiation cross-resistance mechanisms of malignant glioma cells converting the ABC-1 transporter into an attractive pharmacological target for a clinical breakthrough in the therapy of malignant gliomas.
-
7.
ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition.
de Jong, FA, Marsh, S, Mathijssen, RH, King, C, Verweij, J, Sparreboom, A, McLeod, HL
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004;(17):5889-94
Abstract
PURPOSE The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7- ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan. EXPERIMENTAL DESIGN ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies. RESULTS Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng x hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide. CONCLUSIONS The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.