ABCB1 Gene Polymorphisms Research Articles

Association Between ABCB1 Gene Polymorphism and Renal Function in Patients with Hypertension: A Case-Control Study.

BackgroundA previous study found that target organ damage in patients with hypertension was related to genetic factors. The aim of our study aim was to explore the association between the ABCB1 gene and renal function injury induced by hypertension.Material/MethodsWe used a case-control study design. Patients with hypertension were enrolled from our hospital between July 2015 and December 2015. Questionnaire data included personal information, life habits and behavior. Clinical data included blood routine examination and liver and renal function. We used restriction fragment length polymorphism methods for ABCB1 gene polymorphism detection.ResultsThere were 306 patients with hypertension included in the final analyses: 170 cases of hypertension and 136 controls. Compared to controls, the cases group had higher: drinking ratio (65.3% versus 52.9%, p=0.029), body mass index (p=0.032), systolic blood pressure (p<0.001), total cholesterol (p=0.004), blood urea nitrogen (p=0.029), creatinine (p=0.024), uric acid (p=0.011), estimated glomerular filtration rate level (p<0.001), and platelet level (p=0.003). There were no significant differences for others parameters. Genotype frequency distributions of rs1045642 were statistically significant between the two groups (χ2=24.966, p<0.001). No differences were observed for the frequency distribution of rs10808072 and rs1922242 (χ2=1.293, p=0.524; χ2=0.065, p=0.968). The multivariable logistics results found that patients with TT genotype had a higher risk for renal function injury for hypertensive patients compared to those with CC genotype (OR=3.47, 95% CI: 1.19–10.07).ConclusionsOur results suggested that the rs1045642-T allele of the ABCB1 gene may be associated with increased risk for renal function injury in hypertensive patients.

ABCB1 gene polymorphism associated with clinical factors can predict drug-resistant tuberculosis.

Polymorphism in the ABCB1 gene encoding P-glycoprotein, a transmembrane drug efflux pump, contributes to drug resistance and has been widely studied. However, their association with rifampicin and ethambutol resistance in tuberculosis (TB) patients is still unclear. Genotype/allele/haplotype frequencies in c.1236C > T (rs1128503), c.2677G > T/A (rs2032582), and c.3435C > T (rs1045642) were obtained from 218 patients. Of these, 80 patients with rifampicin and/or ethambutol resistance were selected as the case group and 138 patients were selected for the control group through the results of their culture and drug-sensitive tests. Patients aged <18 years and HIV-positive serologic tests were excluded. ABCB1 polymorphisms were determined using a PCR direct-sequencing approach, and restriction fragment length polymorphism (RFLP). A nomogram was constructed to simulate a combined prediction of the probability of anti-TB drug resistance, with factors including genotype c.1236C > T (rs1128503) (P=0.02), clinical form (P=0.03), previous treatment (P=0.01), and skin color (P=0.03), contributing up to 90% chance of developing anti-TB drug resistance. Considering genotype analyses, CT (rs1128503) demonstrated an increased chance of anti-TB drug resistance (odds ratio (OR): 2.34, P=0.02), while the analyses for ethambutol resistance revealed an association with a rare A allele (rs2032582) (OR: 12.91, P=0.01), the haplotype TTC (OR: 5.83, P=0.05), and any haplotype containing the rare A allele (OR: 7.17, P=0.04). ABCB1 gene polymorphisms in association with others risk factors contribute to anti-TB drug resistance, mainly ethambutol. The use of the nomogram described in the present study could contribute to clinical decision-making prior to starting TB treatment.

Loss of constitutive ABCB1 expression in breast cancer associated with worse prognosis.

ABCB1 gene encodes an adenosine 5′-triphosphate–binding cassette transporter, which not only confers multidrug resistance phenotype in malignant cells, but is also present in several nonmalignant tissues. For the last thirty years, ABCB1 expression in breast cancer has been described by many authors, but the extent of expression differs among the studies, and there is no consensus regarding its potential role in carcinogenesis or in the tumor response to antineoplastic drugs. This study aimed to characterize the expression of ABCB1 in breast tumors as a function of genetic, clinical, and histopathological variables. The ABCB1 expression was also evaluated in nonmalignant mammary tissues adjacent to tumors and in benign lesions. The detection of ABCB1 protein was performed by immunohistochemistry in tissue specimens of excised breasts obtained from a prospective cohort of Brazilian women with breast cancer. The association of ABCB1 protein levels with ABCB1 mRNA, gene polymorphisms, and clinical and histopathological variables was also evaluated. The Kaplan–Meier curves and multivariate Cox regression analyses were conducted to identify independent predictors of disease-free survival of patients with breast cancer. ABCB1 was detected in 86.3% (656) of breast tumors, 98.8% (606) of nonmalignant mammary tissue adjacent to tumors, and 100% (28) of benign lesions. Reduced ABCB1 protein levels in breast tumors was associated with triple-negative subtype (adjusted odds ratio [ORadj] =0.24; 95% confidence interval [CI] =0.13–0.45), lymph node status < pN2 (ORadj =0.27; 95% CI =0.10–0.71), tumor size >2 cm (ORadj =0.55; 95% CI =0.32–0.93), and hypertensive status (ORadj =0.42; 95% CI =0.24–0.73), and it was significantly associated with shorter disease-free survival, either for all breast cancer patients (p log-rank =0.012; hazard ratio [HR] =3.46; 95% CI =1.21–9.91) or for those with triple-negative tumors (p log-rank =0.007; HR =11.41; 95% CI =1.29–100.67). The loss of constitutive ABCB1 expression in breast cancer, especially in triple-negative tumors, seems to indicate a subgroup of worse prognosis.

ABCB1 and SLCO1B3 Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population

Background: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. Methods:ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. Results: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. Conclusion: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.

Single nucleotide polymorphisms of ABCB1 gene and response to etanercept treatment in patients with ankylosing spondylitis in a Chinese Han population.

Background:Etanercept was highly recommended for patients with ankylosing spondylitis (AS), as its efficacy has been confirmed in AS, while genetic polymorphisms, by affecting drug metabolism or drug receptor, lead to interindividual variability in drug disposition and efficacy. Therefore, this study aims to investigate whether ABCB1 gene polymorphisms can predict therapeutic response to etanercept in patients with AS.Methods:A total of 185 patients with AS in our hospital were recruited into our study from December 2012 to May 2015. The frequency distributions of genotype and allele of rs2032582, rs1128503, and rs1045642 were detected by polymerase chain reaction (PCR) and electrophoresis verification enzyme products method. AS patients received etanercept treatment for 12 weeks, followed by this would be evaluated by the bath AS disease activity index (BASDAI) score improvement and the assessment of spondyloArthritis international society 20/50/70 (ASAS20/50/70) score improvements to explore the relationship between genotype of ABCB1 gene polymorphisms and therapeutic response to etanercept in patients with AS.Results:After 12 weeks, the BASDAI score mean improvement value of rs2032582 A/A genotype was 2.87 ± 0.52. The ratios of patients with rs2032582 A/A genotype reaching the BASDAI50 and ASAS20 evaluation criteria were 64.29% and 92.86%, respectively. The results indicated that efficacy of etanercept was promoted in rs2032582 A/A genotype. The BASDAI score mean improvement value of rs1128503 C/C genotype was 2.79 ± 0.54 after 12 weeks. The ratios of patients with rs1128503 C/C genotype reaching the BASDAI50 and ASAS20 evaluation criteria were 66.67% and 93.94%, respectively. The results indicated that efficacy of etanercept was promoted in rs1128503 C/C genotype. However, no significant associations were observed between rs1045642 and therapeutic response to etanercept in AS patients.Conclusion:ABCB1 gene rs2032582 and rs1128503 polymorphisms may be associated with the efficacy of etanercept in AS patients. ABCB1 gene polymorphisms can act as biological indicators of etanercept efficacy.

Influence of TS and ABCB1gene polymorphisms on survival outcomes of 5‑FU-based chemotherapy in aChinese population of advanced gastric cancer patients.

To investigate the impacts of gene variations on survival outcomes of advanced gastric cancer (AGC) patients treated with 5‑fluorouracil (5-FU)-based chemotherapy, we analyzed the associations of 2 indels of the TS gene rs34743033 (double or triple tandem repeats of a28 bp sequence in 5'-UTR, denoted as 2R or 3R allele) and rs16430 (a6 bp variation at 1494 bp in 3'-UTR, denoted as ins6 or del6allele) and 2 single nucleotide polymorphisms (SNPs) of ABCB1gene rs2032582 in exon21 and rs1045642 in exon26, with clinical outcomes after 5‑FU treatment. Generally, indels rs34743033 and rs16430 were genotyped by PCR and polyacrylamide gel electrophoresis assay and SNPs rs2032582 and rs1045642 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 110Chinese AGC patients post-chemotherapy. Cox regression analysis was used to analyze the risk factors affecting patient survival. As aresult, rs34743033, rs1045642 and rs2032582 were shown to be significantly associated with overall survival (P< 0.05), and associations between the four polymorphisms with disease-free survival were also observed (P< 0.05). Moreover, we found that genotypes rs34743033 3R/2R, rs16430 ins6/del6, rs1045642 CC or CT, and rs2032582GG were beneficial predictors of clinical treatment outcome in AGC patients, suggesting some clinical implications in chemotherapy of aChinese population.

Genetic Polymorphisms of ABCB1 Gene in Patients Having Resistance to Clopidogrel

Objectives: We sought to study the genetic polymorphisms of ABCB1 gene in post percutaneous coronary intervention (PCI) patients with clopidogrel resistance. Background: Dual antiplatelet therapy (DAPT) is a guideline mandated therapy for patients who undergo PCI. However there exists interindividual variability in drug response to the antiplatelet agents leading to recurrent thrombotic events. Genetic polymorphisms of ABCB1 gene are one among the causes of this interindividual variability. Methods: It is a single center prospective trial and includes221 patients who underwent PCI and were given clopidogrel as a part of DAPT. Platelet reactivity was assessed by grading of platelet activity index (PAI) and considered as high on treatment platelet reactivity (HTPR), i.e., clopidogrel resistance if PAI > 5. Genetic analysis for ABCB1 C-T polymorphism was done by polymerase chain reaction (PCR) and single strand confirmation polymorphism (SSCP) analysis. Results: Amongst 221 patients, 37 (16.7%) patients had ABCB1 C-T polymorphisms. The mean PAI value in these patients was 5.1 ± 3.0, while it was 3.5 ± 2.5 in those patients without ABCB1 C-T polymorphisms (p = 0.004). Compared to patients without HTPR, the occurrence of primary endpoints was not significantly increased in patients with HTPR except for stent thrombosis which was significantly high in patients with HTPR. HTPR was also associated with ABCB1 C-T polymorphisms (p = 0.04), but these polymorphisms did not predict the clinical outcome. Conclusions: There was significant prevalence of ABCB1 C-T polymorphisms in patients with HTPR. However it was not an independent risk factor for clopidogrel resistance and also it did not influence adverse cardiovascular outcomes.

Association of ABCB1 and SLC22A16 Gene Polymorphisms with Incidence of Doxorubicin-Induced Febrile Neutropenia: A Survey of Iranian Breast Cancer Patients.

Breast cancer is the most common cancer in women worldwide. Doxorubicin-based chemotherapy is used to treat breast cancer patients; however, neutropenia is a common hematologic side effect and can be life-threatening. The ABCB1 and SLC22A16 genes encode proteins that are essential for doxorubicin transport. In this study, we explored the effect of 2 common polymorphisms in ABCB1 (rs10276036 C/T) and SLC22A16 (rs12210538 A/G) on the development of grade 3/4 febrile neutropenia in Iranian breast cancer patients. Our results showed no significant association between these polymorphisms and grade 3/4 febrile neutropenia; however, allele C of ABCB1 (rs10276036 C/T) (p = 0.315, OR = 1.500, 95% CI = 0.679–3.312) and allele A of SLC22A16 (rs12210538 A/G) (p = 0.110, OR = 2.984, 95% CI = 0.743–11.988) tended to have a greater association with grade 3/4 febrile neutropenia, whereas allele T of ABCB1 (rs10276036) (p = 0.130, OR = 0.515, 95% CI = 0.217–1.223) and allele G of SLC22A16 (rs12210538) (p = 0.548, OR = 0.786, 95% CI = 0.358–1.726) tended to protect against this condition. In addition to breast cancer, a statistically significant association was also observed between the development of grade 3/4 febrile neutropenia and other clinical manifestations such as stage IIIC cancer (p = 0.037) and other diseases (p = 0.026). Our results indicate that evaluation of the risk of grade 3/4 neutropenia development and consideration of molecular and clinical findings may be of value when screening for high-risk breast cancer patients.

Association of ABCB1 gene polymorphisms with aspirin resistance in patients with ischemic stroke

Objective: To investigate the relationship of single nucleotide polymorphisms of Multi-drug resistance (ABCB1/MDR1) gene with Aspirin resistance (AR) in patients with ischemic stroke. Methods: Three hundred ischemic stroke patients from Department of Neurology, Affiliated Hospital of Qingdao University were collected from September 2014 to May 2016. According to the results of Thromboelastogram (TEG), the patients were divided into aspirin resistance (AR) group and aspirin sensitive (AS) group. The genotypes of ABCB1 gene (C1236T, G2677T/A, C3435T) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Result: Linkage disequilibrium was found among the three loci (D'=0.8; r2=0.9). The T allele frequency of C3435T in AR group and AS group was 57.3% and 43.1% respectively, and the difference was statistically significant (χ2=9.143, P=0.002). The frequency of genotypes CT+ TT in AR group was higher than AS group, and the difference was also significant (χ2=4.369, P=0.037). But there was no difference in allele frequency and genotype distribution of C1236T and G2677T/A between the two groups.Haplotypes constituted by the three loci were analyzed, and the OR value of haplotype (C-T-T) was 1.602 (χ2=5.374, P=0.02), the OR value of haplotype (C-G-C) was 0.495 (χ2=8.775, P=0.003), the OR value of haplotype (T-G-C) was 3.010 (χ2=5.846, P=0.015), while the OR value of haplotype (T-T-T) was 3.308 (χ2=4.650, P=0.031). Conclusions: The polymorphisms of C3435T in the ABCB1 gene have a relationship with AR in the patients with ischemic stroke. The haplotypes (C-T-T, T-G-C, T-T-T) are also related to the AR in the patients with ischemic stroke.

Prognostic Value and Implication for Chemotherapy Treatment of ABCB1 in Epithelial Ovarian Cancer: A Meta-Analysis.

BackgroundChemotherapy resistance is reported to correlate with up-regulation of anti-tumor agent transporter ABCB1 (p-gp) in epithelial ovarian cancer (EOC), but the results remain controversial. To reconcile the results, a systematic review followed by meta-analysis was performed to assess the association between high ABCB1 status or ABCB1 gene variants and overall survival (OS), progression free survival (PFS), and total response rate (TR) in patients with EOC.Materials and MethodsElectronic searches were performed using Pubmed, EMBASE, Web of Science and Chinese Wanfang databases from January 1990 to February 2016. Summary hazard ratio (HR), risk ratio (RR) and 95% confidence intervals (CIs) were combined using fixed or random-effects models as appropriate.ResultsThirty-eight retrospective studies of 8607 cases qualified for meta-analysis were identified. Our results suggested that ABCB1 over-expression was significantly associated with unfavorable OS (HR = 1.54; 95% CI, 1.25–1.90), PFS (HR = 1.49; 95% CI, 1.22–1.82) and TR (RR = 0.63; 95% CI, 0.54–0.75). After adjustment for age, clinical stage, residual disease, histological type and tumor grade, high ABCB1 status remained to be a significant risk factor for adverse OS and PFS. Patients with recurrent ABCB1 positivity suffered from poorer OS than those with primary ABCB1 positivity. However, stratified by chemotherapy regimen, inverse correlation between high ABCB1 status and poor OS, PFS and TR were only found in patients underwent platinum-based chemotherapy but not in patients received standard platinum/paclitaxel-based chemotherapy. No evidence was found for any association between ABCB1 gene polymorphisms and OS, PFS or TR.ConclusionHigh ABCB1 status is significantly associated with chemo-resistance and poor prognosis in patients with EOC. Large-scale, prospective studies are needed to assess the clinical value of ABCB1 expression in EOC more accurately.

Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients.

Anastrozole, an aromatase inhibitor widely used in breast cancer, has recently been indicated to be a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series. This study included 110 postmenopausal women with hormone receptor-positive breast cancer. Anastrozole plasma levels were determined by a liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry system. Patients were genotyped for SNPs in the ABCB1, TCL1A and CYP19A1 genes to search for associations with pharmacokinetic and pharmacodynamics parameters using logistic regression models. Anastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95±11.91ngml-1 ). The ABCB1 2677-TT genotype was associated with higher plasma levels (32.22±12.82 vs. 25.86±11.56ngml-1 for GG/GT subjects; 95% confidence interval: -12.3 to -0.40), whilst the 3435-TT genotype showed a protective effect on the risk of arthralgia (odds ratio =0.32 [0.11-0.89]; P=0.029). The CYP19A1 rs1008805 GG genotype was strongly and inversely associated with arthralgia (odds ratio=0.24 [0.09-0.65], P=0.004); however, SNPs near the TCL1A gene were not linked to this adverse effect. None of the patients who had cancer recurrence harboured the CYP19A1 rs727479 AA genotype, which, in contrast, was present in 38% of patients who did not relapse (P for trend=0.031). Our findings indicate that variability in anastrozole plasma levels may be attributable to the status of the ABCB1 gene locus. Furthermore, genetic variants in CYP19A1 were associated with arthralgia and cancer recurrence in our patients.

ABCB1 polymorphisms and steroid treatment in children with idiopathic nephrotic syndrome

Background: The most common cause of nephrotic syndrome (NS) is idiopathic nephrotic syndrome (INS), also called nephrosis. Although most patients respond to steroid therapy, there is unequal response to treatment suggesting the involvement of genetic factors. The current study was conducted to evaluate the influence of two single nucleotide polymorphisms (SNPs) in ABCB1 (C3435T and C1236T) on the steroid treatment response in INS children.Materials and methods: Genotyping of ABCB1 C3435T and C1236T polymorphisms by real time PCR were conducted on 120 INS children, 80 steroid sensitive (SS) and 40 steroid resistant (SR).Results: A significant difference in the distribution of ABCB1 C3435T and C1236T genotypes was observed between SS and SR patients. C1236T polymorphism was associated with steroid resistance in INS children (odds ratio: 2.27, 95 % confidence interval: 1.2–4.4; P = 0.012). The frequency of the T allele was significantly higher in SR than in SS patients (81.2 vs. 65.6%, respectively). The odds ratio for the C3435T polymorphism in response to steroid treatment was smaller than that of the polymorphism C1236T, and did not reach statistical significance (odds ratio: 1.1, 95 % confidence interval: 0.6–1.9; P = 0.77).Conclusion: Our results suggested that C1236T polymorphism in ABCB1 gene was associated with steroid resistance. A higher proportion of SR children had C1236T TT genotype and T allele, these patients may require other therapeutic strategies.

288P - Effect of ABCB1 gene polymorphisms C3435T and C1236T on tumour response and plasma levels of docetaxel in locally-advanced breast cancer patients of South India receiving neo-adjuvant chemotherapy

Variable response to docetaxel, which is given in locally-advanced breast cancer (LABC) patients as a part of neo-adjuvant chemotherapy (NACT), had been reported. This altered response could be due to polymorphisms in the gene (ABCB1) coding for the efflux transporter ABCB1 (MDR1). Objectives: · To evaluate the effect of single nucleotide polymorphisms (SNPs) C3435T (rs1045642) and C1236T (rs1128503) in ABCB1 gene on the tumor response in LABC patients of South India receiving docetaxel as NACT. · To determine the effect of these SNPs on plasma levels of docetaxel. Tumour response to docetaxel was evaluated in 129 LABC patients, out of which plasma levels of docetaxel were estimated in 74. Blood samples were collected at the end of infusion and 1 hour later. DNA was extracted by ‘phenol-chloroform extraction method’ from the leucocytes. Genotyping was performed with RT-PCR System. Tumor response was assessed by RECIST criteria. Plasma levels of docetaxel were estimated by LCMS/MS. Patients with “CT/TT” genotypes (response rate: 66%) of ABCB1 gene (C1236T) showed better tumor response than those with “CC” genotype (response rate: 13%) [OR = 2.94 (CI: 1.15 - 7.52); p = 0.032]. The superior response in “CT/TT” genotypes can be attributed to the presence of “T” allele causing altered function of ABCB1 gene coding for MDR1 transporter. Plasma levels of docetaxel were also in line with the tumor response in “CT/TT” genotypes of ABCB1 gene (C1236T). Mean of the plasma concentration ratios (C0/C1) of docetaxel in “CT/TT” genotypes (13.49 ± 6.48 ng/mL) were significantly higher than those of the “CC” genotype (8.19 ± 3.10 ng/mL) [p = 0.003]. In contrast, the genotypes of C3435T in ABCB1 gene were not found to significantly influence the tumor response or the plasma levels of docetaxel. These results suggest that ABCB1 C1236T polymorphism could significantly influence the treatment response to docetaxel and the plasma levels of docetaxel. Hence, our study emphasizes the importance of ABCB1 genotyping for individualization of docetaxel pharmacotherapy in breast cancer patients.

OP.6D.05] INFLUENCE OF MULTIDRUG RESISTANCE P-GLYCOPROTEIN GENE POLYMORPHISM OR INHBITION ON PLASMA ALDOSTERONE CONCENTRATION IN HEALTHY SUBJECTS

Objective: The multidrug resistance P-glycoprotein (P-gp) has been shown to contribute to the secretion of aldosterone by human adrenal cells in vitro. To address the clinical relevance of this finding, we studied the impact of a loss of function P-gp polymorphism of ABCB1 gene and of clarithromycin, a P-gp inhibitor, on plasma aldosterone (PAC) and renin (PRC) concentrations in heathy subjects. Design and method: Three groups of 20 healthy normotensive male volunteers were selected on the basis of their ABCB1 genotype: CC non carriers, heterozygous CT and TT homozygous carriers of haplotype 2677–3435. PAC, PRC and urinary aldosterone excretionwere measured at 09:00 in semi-recumbent position and on ad libitum sodium diet at baseline and after 5-day treatment with the P-gp inhibitor, clarithromycin (200 MG bid). Results: Age, BMI, blood pressure, plasma Na and K concentrations, PAC and UAE (urinary adlosterone excretion) did not differ among the genotypes. There was a trend for an increase in PRC between CC, CT and TT subjects with a significantly higher PRC in TT than in CC subjects (mean difference: + 34% [95%CI%: 4–50%], p = 0.0295). PRC, PAC and UAE were not affected by clarithromycin in the CC group (p = 0.2746, 0.2860 and 0.2274, respectively), or in the CT and TT groups.Conclusions: The 2677–3435 P-gp haplotype and Pg-p inhibition were not associated with significant differences in aldosterone secretion in physiological conditions on a normal sodium intake in healthy subjects. The slightly higher PRC in homozygous carrier TT subjects than in non-carrier CC subjects may reflect a subtle impairment of aldosterone secretion. Whether this subtle abnormality on steady state may predict an impaired adaption of aldosterone secretion in pathophysiological conditions remains to be established.

Association between ABCB1 C3435T polymorphism and breast cancer risk: a Moroccan case-control study and meta-analysis.

BackgroundBreast cancer is the most common cause of cancer death among women. Several studies have investigated the relationship between the C3435T polymorphism of ABCB1 gene and risk of breast cancer; but the results are conflicting. In the present study, we sought to assess the relationship between the C3435T polymorphism in ABCB1 gene and the risk of breast cancer in a sample of the Moroccan population.MethodsA case control study was performed on 60 breast cancer patients and 68 healthy women. The ABCB1 C3435T polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Furthermore, a meta-analysis including 16 studies with 6094 cases of breast cancer and 8646 controls was performed.ResultsGenotype frequencies were 50 % for CC, 33.3 % for CT and 16.7 % for TT in patients and 41.2 % for CC, 48.5 % for CT and 10.3 % for TT respectively in the control group. This difference was not statistically significant. The same trend as observed in the allele distribution between patients and controls (P = 0.84). Findings from the meta-analysis showed that the ABCB1 C3435T polymorphism was not associated with an increased risk of breast cancer in the dominant model (OR = 0.907; 95 % CI = 0.767–1.073; P = 0.25) as well as in the recessive model (OR = 1.181; 95 % CI = 0.973–1.434; P = 0.093) and in the allele contrast model (OR = 1.098; 95 % CI = 0.972–1.240; P = 0.133). However, the stratification of studies on ethnic basis showed that the TT genotype was associated with the risk of breast cancer in Asians (OR = 1.405; 95 % CI = 1.145–1.725; P = 0.001), Caucasians (OR = 1.093; 95 % CI = 1.001–1.194; P = 0.048) and North African (OR = 2.028; 95 % CI = 1.220–3.371; P = 0.006).ConclusionsWe have noted that the implication of C3435T variant on the risk of breast cancer was ethnicity-dependent. However, there is no evidence that ABCB1 C3435T polymorphism could play a role in susceptibility to breast cancer in Morocco. Further studies with a larger sample size, extended to other polymorphisms are needed to understand the influence of ABCB1 genetic variants on the risk of breast cancer.

Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non-small cell lung cancer patients

Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3⿿4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman® probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3⿿4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy.

One-Year Follow-up of Children and Adolescents with Major Depressive Disorder: Relationship between Clinical Variables and Abcb1 Gene Polymorphisms.

Introduction: Differences in response to fluoxetine (FLX) may be influenced by certain genes that are involved in FLX transportation (ABCB1). We examined remission and recovery from the index episode in a cohort of patients treated with FLX, and also investigated associations between genetic variants in ABCB1 and remission, recovery, and suicide risk. Methods: This was a naturalistic 1-year follow-up study of 46 adolescents diagnosed with major depressive disorder (MDD). At 12 months they underwent a diagnostic interview with the K-SADS-PL. Results: It was found that remission was around 69.5% and recovery 56.5%. Remission and recovery were associated with lower scores on the CDI at baseline, with fewer readmissions and suicide attempts, and with lower scores on the CGI and higher scores on the GAF scale. No relationship was found between ABCB1 and remission or recovery. However, a significant association was observed between the G2677T ABCB1 polymorphism and suicide attempts. Conclusion: Other factors such as stressful events, family support, and other genetic factors are likely to be involved in MDD outcome.

Effect of ABCB1 rs12720464 and rs1055302 polymorphisms in Chinese patients on the time course of action of rocuronium administered as a single dose.

To determine whether ABCB1 gene polymorphisms affect the time course of action of rocuronium in Chinese patients. This study included 105 unrelated Chinese patients undergoing general anesthesia with propofol, fentanyl, and rocuronium. Neuromuscular monitoring was performed with calibrated acceleromyography. Patients were allowed to recover spontaneously from the neuromuscular block. The time interval between the first maximum depression of the train of four (TOF) and spontaneous recovery TOF ratio of 0.25/0.7/0.8/0.9 was recorded. The Sequenom MassArray® single-nucleotide polymorphism (SNP) detection technology was used to detect the genotypes of the ABCB1 rs12720464, rs1055302. Demographic and non-genetic clinical data were also collected. In the present study, the mean time to spontaneous recovery of TOF ratio 0.8/0.9 in ABCB1 rs12720464 GG genotype was longer compared to that observed in ABCB1 rs12720464 AG genotype (56.77 ± 14.23 minutes vs. 49.50 ± 10.49 minutes, and 62.58 ± 18.16 minutes vs. 53.20 ± 12.56 minutes, respectively, p < 0.05). Further, the time to spontaneous recovery of TOF 0.7/0.8/0.9 in ABCB1 rs1055302 GG genotype was longer than that in ABCB1 rs1055302 AG genotype (52.00 ± 12.10 minutes vs. 44.83 ± 7.38 minutes, 55.96 ± 13.92 minutes vs. 46.83 ± 7.67 minutes, 61.66 ± 17.70 minutes vs. 49.50 ± 8.44 minutes, respectively, p < 0.05). In Chinese patients who were administered a single dose of rocuronium, the genetic variants ABCB1 rs12720464, and rs1055302 contribute to the individual< variability of time course of action.

Monitoring the Intracellular Tacrolimus Concentration in Kidney Transplant Recipients with Stable Graft Function.

Although monitoring the intracellular concentration of immunosuppressive agents may be a promising approach to individualizing the therapy after organ transplantation, additional studies on this issue are needed prior to its clinical approval. We investigated the relationship between intracellular and whole blood concentrations of tacrolimus (IC-TAC and WB-TAC, respectively), the factors affecting this relationship, and the risk of rejection based upon IC-TAC in stable kidney recipients. Both IC-TAC and WB-TAC were measured simultaneously in 213 kidney recipients with stable graft function using LC-MS/MS. The tacrolimus ratio was defined as IC-TAC per WB-TAC. The genetic polymorphism of ABCB1 gene and flow cytometric analyses were conducted to probe the correlation between tacrolimus concentrations and the immunoreactivity status as a potential risk of rejection, respectively. The correlation between IC-TAC and WB-TAC was relatively linear (r = 0.67; P<0.001). The factors affecting the tacrolimus ratio were sex, hematocrit, and the transplant duration, as follows: a high tacrolimus ratio was noted in female patients, patients with a low hematocrit, and patients with a short transplant period. However, the tacrolimus ratio did not reflect the prior clinical outcomes (e.g., rejection) or the genetic polymorphism of ABCB1. After stimulation with phorbol-12-myristate 13-acetate and ionomycin, the proportion of T cells producing interferon-gamma or interleukin-2 was higher in the low-IC-TAC group than in the high-IC-TAC group. Further studies are required to evaluate the value of the intracellular tacrolimus concentrations in several clinical settings, such as rejection, infection, and drug toxicity.

Impacts of ABCB1 (G1199A) polymorphism on resistance, uptake, and efflux to steroid drugs

1. P-glycoprotein (P-gp) substrates, including steroid drugs, involve in the inter-individual differences in resistant phenotype. This study was performed to evaluate whether G1199A polymorphism in ABCB1 gene can alter the sensitivity, accumulation, and transepithelial efflux to steroids in LLC-PK1 cells.2. The stable recombinant LLC-PK1 cell lines transfected with ABCB1 1199G and ABCB1 1199A were used to assess the sensitivity, accumulation, and transepithelial permeability to steroids.3. The cells transfected with 1199A allele displayed stronger resistance to aldosterone, dexamethasone, and cortisol (2.5-, 2.0-, and 1.6-fold, respectively) than cells overexpressing 1199G allele, while the two types of recombinant cells showed a similar resistance to corticosterone. The accumulation of aldosterone, dexamethasone, and cortisol in recombinant 1199A cells were significantly decreased when compared to 1199G cells (2.9-, 4.4-, and 3.9-fold, respectively). The net efflux ratios of P-gp-mediated aldosterone, dexamethasone, and cortisol in cells expressing 1199A allele were apparently greater than cells transfected with 1199G allele (3.3-, 3.5-, and 4.0-fold, respectively).4. The impacts of ABCB1 (G1199A) single nucleotide polymorphism on the efflux of P-gp substrates presented as drug-specific. Overall, the transport ability of P-gp-dependent steroid drugs in recombinant model overexpressing variant 1199A allele is stronger in comparison to cells overexpressing wild-type 1199G allele. Therefore, the ABCB1 (G1199A) polymorphism may affect effective steroids concentration in target cells by regulating the drug transport and distribution.