The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >/=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >/=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >/=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain

Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170.METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses.RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45).CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.</p

Role of ABCB1 C3435T variant in response to antiepileptic drugs in epilepsy: a review

Over-expression of P-glycoprotein (P-gp), the encoded product of the ATP-binding cassette (ABC), sub-family B, member 1 (ABCB1/MDR1) gene, plays an important role in mediating multidrug resistance to antiepileptic drugs (AEDs) in about 30% of patients with epilepsy. Genetic variation may in part explain inter-individual differences in phenotype-genotype relationships in the pharmacological response of epilepsy patients to AEDs. The synonymous C3435T polymorphism is one of the most common allelic variants in the ABCB1/MDR1 gene, proposed in the causation of refractory epilepsy. Many studies have shown the relationship between C3435T polymorphism and refractoriness to AEDs in epilepsy. However, there is controversy between the findings of various studies, that is, whether ABCB1/MDR1 C3435T gene polymorphism is associated with response to AEDs in epilepsy patients. This review provides a background and discusses the results of investigations on possible confounding factors affecting the interpretation and implementation of association studies in this area

ABCB1-C3435T polymorphism and breast cancer risk: A case-control study and a meta-analysis

Purpose: To investigate the association of ABCB1-C3435T transition with breast cancer risk which was followed by a meta-analysis. Methods: In a case-control study we collected blood samples from 290 women (including 150 breast cancer patients and 140 healthy controls). ABCB1-C3435T genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A meta-analysis was performed for a total of 13 eligible studies involving 5,835 cases and 8,178 controls. Results: The results of case-control study revealed a significant association between T allele (OR=1.770, 95%CI=1.236-2.535, p=0.002), CT genotype (OR=1.661, 95%CI=1.017-2.713, p=0.042), and TT genotype (OR=3.399, 95%C1=1.409-8.197, p=0.006) with breast cancer risk. Data from meta-analysis revealed a significant association between ABCB1-C3435T polymorphism and breast cancer risk in allelic (OR=1.243, 95%CI=1.079-1.432, p=0.003), co-dominant (OR=1.349, 95%CI=1.042-1.746, p=0.023), dominant (OR=1.204, 95%CI=1.019-1.422, p=0.029), and recessive (OR=1.226, 9S%C1-1.0U-1.488, p=0.039) models. Conclusions: The results suggest that the ABCB1-C3435T gene polymorphism might be a genetic risk factor and a potential biomarker for breast cancer

Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male Portuguese individuals

Major depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus–pituitary–adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR) = 0.360, 95% confidence interval [CI]: [0.140– 0.950], p = 0.022; C3435T: OR= 0.306, 95% CI: [0.096–0.980], p = 0.042; and G2677TA: OR= 0.300, 95% CI: [0.100– 0.870], p = 0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR = 0.313, 95% CI: [0.118–0.832], p = 0.016, FDR p = 0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood&ndash;brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11&thinsp;mg of ESC to remit, whereas TC and CC carriers required 24 and 19&thinsp;mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5&ndash;3.4; P&lt;0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72&ndash;25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.<br /

Study of ABCB1 polymorphism (C3435T) in HIV-1-infected individuals from South India

Studies on P-glycoprotein expression and function have revealed that a single nucleotide polymorphism (SNP) in the human ABCB1 gene at 3435 (C > T) results in altered expression and function of P-glycoprotein [1, 2].There have been reports of lower nelfinavir and efavirenz (EFV) concentrations associated with TT genotypes (mutant) of ABCB1 C3435T polymorphism [3, 4].Frequency distribution of this polymorphism is known to vary across populations [3, 5, 6]. We report the genotype distribution of ABCB1 C3435T in 179 individuals (126 HIV-infected and 53 healthy) from South India. The polymorphism was correlated with plasma 12 h EFV and 2 h nevirapine (NVP) concentrations in 55 and 71 patients, respectively. Plasma EFV and NVP were estimated by HPLC [7, 8]. Genotyping was carried out by PCR-RFLP [9]

Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

Polymorphisms of ABC transporters and their role in cancer cells

ABC transporteri su membranski proteini koji omogućuju prijenos različitih tvari kroz membranu i kao takvi su nužni u održavanju integriteta i homeostaze cjelokuponog metabolizma. Ti proteini se sastoje od više domena, a upravo je interakcija među domenama i njihova konformacijska promjena ključna u procesu prijenosa tvari, a kao glavni pokretač je energija dobivena hidrolizom ATP-a koja uzrokuje tu konformacijsku promjenu. S obzirom na homologiju domena, geni ABC porodice se mogu svrstati u 7 potporodica koje obnašaju različite funkcije u organizmu i zastupljene su u različitim stanicama i tkivima organizma. Različite vrste ABC transportera su odgovorne za prijenos supstrata koji mogu biti heterogene strukture, podrijetla i funkcije u organizmu. Iako sudjeluju u prijenosu endogeno sintetiziranih supstrata kao i stranih tvari, prvenstveno su otkriveni na temelju uloge u uklanjanju protutumorskih lijekova iz tumorskih stanica zbog čega smanjuju efikasnost liječenja tumora. Na efikasnost liječenja tumora utječu, osim lijekova i neki drugi čimbenici organizma kao što su i polimorfizmi ABC transportera. Različite genske varijante za određeni protein utječu na njegovu pojavnost i mogućnost obavljanja funkcije u organizmu. Tako je na temelju istraživanja različitih malignih bolesti u ljudi pokazano da različite genske varijante ABC transportera utječu na ishode liječenja bilo da povećavaju ili smanjuju mogućnosti ozdravljenja. Daljnja istraživanja će doprinijeti razumijevanju polimorfizama u ABC transporterima i njihovu funkciju u prijenosu tvari kroz membranu te na taj način omogućiti kvalitetniji pristup u liječenju malignih bolesti.ABC transporters are transmembrane proteins that enable translocation of various substances across cellular membranes, and as such are essential in maintaining integrity and homeostasis of whole metabolism. These proteins are composed of multiple domains, and interactions between domains and their conformational changes are crucial in translocation process. These transbembrane proteins utilize energy by hydrolysis of ATP, which causes a conformational change. ABC gene family are classified based on domain homology into seven subfamilies. Different ABC transporter proteins perform different functions in the body and are present in different cells and tissues of the body. Different types of ABC transporters are responsible for the transfer of substrates with heterogeneous structure, origin and function in the cell. Although they participate in the transfer of endogenously synthesized substrates and the foreign substances, they were primarily discovered because of their role in the removal of anticancer drugs from tumor cells thereby reducing the efficiency of tumor ttreatment. Efficiency of the treatment of tumors affects other than drugs, and other factors such as cell physiological condition and polymorphisms of ABC transporters. Different genetic variant coding for a particular protein affect its conformation and the possibility of maintaining its function in cells. Research based on various malignancies in humans has shown that different gene variants of ABC transporters affect outcomes - either increase or decrease treatment efficiency. Further research should contribute to understanding polymorphisms in ABC transporters and their function in translocation mechanisms across the membrane and thus allow better understanding and more efficient treatment of malignant diseases