BACKGROUND: The burden of chronic kidney disease (CKD) and kidney failure in Ghana is on the ascendency, with the prevalence of CKD estimated at 13.3%. Patients with CKD who progress to kidney failure require life sustaining kidney replacement therapy (KRT) which is almost exclusively available in Ghana as haemodialysis. Kidney transplantation is considered the best KRT option for patients with irreversible kidney failure due to its relative cost efficiency as well as its superiority in terms of survival and quality of life. However, because transplants may trigger an immune response with potential organ rejection, immunosuppressants such as tacrolimus dosing are required.
OBJECTIVE: This study sought to determine single nucleotide polymorphisms in CYP3A5, CYP3A4 and MDR1 genes that affect the pharmacokinetics of Tacrolimus in a population of Ghanaian patients with kidney failure.
METHODS: This cross-sectional study comprised of 82 kidney failure patients undergoing maintenance haemodialysis at the Renal and Dialysis unit of Korle-Bu Teaching Hospital (KBTH). Clinical and demographic data were collected and genomic DNA isolated. Samples were genotyped for specific SNPs using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP).
RESULTS: Participants, 58/82 (70.73%) harbored the wildtype CYP3A5*1/*1 AA genotype, 20/82 (24.39%) carried the heterozygous CYP3A5*1/*3 AG genotype, and 4/82 (4.88%) had the homozygous mutant CYP3A5*3/*3 GG genotype. Also, 6/82 (7.32%) carried the wildtype AA genotype, 11/82 (13.41%) had the heterozygous AG genotype, and 65/82 (79.27%) harbored the homozygous mutant GG genotype of CYP3A4*1B (-290 A>G). For MDR1_Ex21 (2677 G>T), 81/82 (98.78%) carried the wildtype GG genotype, while 1/82 (1.22%) had the heterozygous GT genotype. For MDR1_Ex26 (3435 C>T), 63/82 (76.83%) had the wildtype CC genotype, while 18/82 (21.95%) carried the heterozygous CT genotype, and 1/82 (1.22%) harbored the mutant TT genotype.
CONCLUSIONS: SNPs in CYP3A4, CYP3A5, and MDR1 genes in a population of Ghanaian kidney failure patients were described. The varying SNPs of the featured genes suggest the need to consider the genetic status of Ghanaians kidney failure patients prior to transplantation and tacrolimus therapy.

The relapses and refractory disease are a challenge in the management of patients with Takayasu arteritis (TAK). We quantified pathogenic CD4 + memory T helper cells bearing surface markers CD161 and/or p-glycoprotein (MDR1) in patients with TAK. Peripheral blood mononuclear cells of 21 patients with TAK and 16 age-matched controls were stained with anti-CD3, anti-CD4, anti-CD45RA, anti-CD161 and anti-p-glycoprotein antibodies and subjected to flow cytometry by FACS ARIAIII. Eighteen patients underwent follow-up immunophenotyping. Intracellular staining for interleukin-17 and interferon-γ was performed for 18 patients and 11 controls. Surgical arterial biopsies of 6 TAK and 5 non-inflammatory controls were subjected to immunohistochemistry with anti-CD161 and anti-p-glycoprotein. At baseline the frequency of MDR1 + CD4 + and CD161 + MDR1 + CD4 + memory T cells was higher in TAK than controls (p = 0.002 and 0.01, respectively). After stimulation, the frequency of IFN-y + CD161 + cells was higher in TAK than controls (p = 0.028). Modal fluorescence intensity of CD161 + MDR1 + CD45RA - CD4 + cells was higher in active as compared with stable disease (p = 0.041). At 6 months, MDR1 + and CD161 + MDR1 + memory CD4 + T cells decreased significantly only in patients who had complete/partial response to treatment (p = 0.047 and 0.02, respectively). To conclude, MDR1 + and MDR1 + CD161 + CD4 + memory T-helper cells are increased in patients with TAK. These cells decreased only in patients with response to treatment during subsequent follow-up.

UNASSIGNED: Resistance to antiepileptic drugs (AEDs) remains one of the main challenges to neurologists. Polymorphisms of drug efflux transporters such as multidrug resistance (MDR1) gene and target sites such as the nucleus accumbens-associated 1 (NAC1) gene have been suggested to influence the responsiveness to treatment.
UNASSIGNED: Evaluation of the association of MDR1 and NAC1 polymorphisms with AEDs resistance among Jordanian epileptic patients.
UNASSIGNED: 86 Jordanian epileptics were included in the study. DNA was extracted and genotyping was conducted by polymerase chain reaction followed by sequencing. Nine single nucleotide polymorphisms (SNPs) on the MDR1 gene and six SNPs on the NAC1 gene were investigated.
UNASSIGNED: MDR1 and NAC1 polymorphisms don\'t seem to influence the resistance to AEDs at the genotype or allele level. However, a strong association was found between MDR1 rs2032588 (OR = 5; 95%CI = [1.3-18.8], p = 0.01) and AEDs resistance among males at the allele level. Also, data revealed an association between MDR1 rs1128503 and AEDs resistance among females at the allele level.
UNASSIGNED: The data suggest that MDR1 and NAC1 polymorphisms do not influence the AEDs resistance among Jordanian epileptics. However, there is a gender-dependent association between MDR1 polymorphisms and resistance to AEDs at two SNPs (rs2032588 and rs1128503).

OBJECTIVE: Candida albicans is a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML). Prolonged use of fluconazole as empirical antifungal prophylaxis in AML patients leads to overexpression of efflux pump genes that resulted in the emergence of azole-resistant species. Consequently, the introduction of a new strategy to improve the management of C. albicans infections is an urgent need. Nonsteroidal anti-inflammatory drug (NSAID) ketorolac is associated with a reduction in cancer relapses. The present study was performed to investigate the use of ketorolac-fluconazole combination to reverse fluconazole resistance in C. albicans isolated from AML patients on induction chemotherapy.
METHODS: One hundred and seventy AML patients were evaluated. Fifty C. albicans were isolated and subjected to disc diffusion assay and broth microdilution for fluconazole alone and combined with different concentrations of ketorolac. Efflux pump gene (CDR1, CDR2, and MDR1) expressions were quantified by real-time PCR.
RESULTS: The tested ketorolac acted synergistically with fluconazole against resistant C. albicans with the minimum inhibitory concentration (MIC) of fluconazole decreased from >160 μg/mL to 0.3-1.25 μg/mL in (93.8%) of resistant isolates with fractional inhibitory concentration index (FICI) value of 0.25. The majority of the resistant isolates overexpressed CDR1 (71.1%) and MDR1 (60%).
CONCLUSIONS: Ketorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy.

The multidrug resistance 1 (MDR1) gene plays an important function in carcinogens detoxification and drugs metabolism. Many authors reported that MDR1 gene influences individual susceptibility to cancers. We carried out the present case-control study to investigate the impact of MDR1 gene in the predisposition to acute myeloid leukemia (AML) in a sample of Moroccan population. In addition, we performed a meta-analysis study to discuss our results and to better highlight the influence of MDR1 gene on the susceptibility of AML.
The study included 187 AML patients and 206 controls. Genomic DNA was extracted from white blood cell by salting method. Polymorphisms of G2677 T and C3435 T were genotyped by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), using Mbo I and Ban I restriction enzymes. Statistical analysis was performed using the software SPSS (version 19.0; SPPS Inc., Chicago, IL, USA) and MedCalcv.11.6.1.0 software.
No statistically significant differences in genotype and allelic distribution were found in G2677 T and C3435 T polymorphisms between AML cases and controls in the Moroccan population. On the other hand, we found that the age of onset of AML in patients with homozygous mutant genotype was statistically lower than in patients with either the heterozygous or wild type genotype for both polymorphisms (P = 0.006; P = 0.03). Meta-analysis showed a significant association of C3435 T, G2677 T polymorphisms on the susceptibility of AML when considering the recessive and the allelic models.
Our findings showed that the G2677 T and C3435 T polymorphisms of the MDR1 gene were associated with the age at onset of AML in our population. In addition, the meta-analysis showed that these polymorphisms could play a role in susceptibility to AML.

The multidrug resistance 1 gene (MDR1) encodes for P-glycoprotein (P-gp), which plays a pathophysiological role in the development of autoimmune diseases, including systemic lupus erythematosus (SLE). Herein, we aimed to investigate the relationship between MDR1 gene polymorphisms and SLE susceptibility in the Chinese Guangxi population. The genotypes of rs1128503 and rs1045642 in MDR1 gene were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method in 283 SLE patients and 247 healthy controls from Guangxi. Direct sequencing method was used to verify the results. Binary logistic regression analyses adjusting for gender and age indicated that subjects carrying the rs1128503 T-allele and TT genotype were at increased risk of SLE when compared to carriers of the C allele and CC genotype, with adjusted ORs of 1.36 (95% CI 1.07-1.74; P = 0.014) and 1.77 (95% CI 1.08-2.88; P = 0.022), respectively. In addition, the risk allele T had a recessive effect (OR 1.49, 95% CI 1.04-2.14, P = 0.029). Subgroup analyses revealed effect modification by age for the presence of the rs1128503 T allele, yielding a significant positive association with SLE in older (≥40 years) subjects (T vs. C allele: OR 1.41, 95% CI 1.01-1.96; P = 0.041; TT vs. CC genotype: OR 1.74, 95% CI 1.07-2.79; P = 0.021). For the first time, we demonstrated that MDR1 rs1128503 polymorphisms were associated with SLE susceptibility in Chinese Guangxi population.

OBJECTIVE: Hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). To gain a better understanding of the pathogenesis of HBV infection, this study aimed to investigate the differentially expressed proteins (DEPs) in liver tissues from patients with chronic hepatitis B (CHB) infection.
RESULTS: Seventy-one DEPs were identified. Overexpression of multi-drug resistance protein 1 (MDR1) was validated by RT-qPCR and western blot analyses. Moreover, its expression was increased at both the mRNA and protein levels in response to overexpression of HBV large surface protein (LHBs). Furthermore, screening of transcription factors suggested the possible involvement of hypoxia-inducible factor 1α (HIF-1α) in the interaction between LHBs and MDR1. The function of HIF-1α in the MDR1 activation was confirmed by EMSA and reporter gene analyses.
METHODS: Liver samples from CHB patients and controls without HBV infection were collected and subjected to isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometric analysis.
CONCLUSIONS: These results imply that LHBs, in association with HIF-1α, induces MDR1 overexpression, which may contribute to the pathogenic changes in CHB infection.

Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors. In this study we assessed the heritability of the pharmacokinetics of talinolol as a putative probe drug for MDR1 and possibly other membrane transporters.
Talinolol pharmacokinetics were investigated in a repeated dose study in 42 monozygotic and 13 same-sex dizygotic twin pairs. The oral clearance of talinolol was predefined as the primary parameter. Heritability was analyzed by structural equation modeling and by within- and between-subject variance and talinolol clearance was correlated with polymorphisms in MDR1, MRP2, BCRP, MDR5, OATP1B1, and OCT1.
Talinolol clearance varied approximately ninefold in the studied sample of healthy volunteers. The correlation of clearances between siblings was not significantly different for the monozygotic and dizygotic pairs. All data analyses consistently showed that variation of talinolol pharmacokinetics was mainly determined by environmental effects. Structural equation modeling attributed 53.5 % of the variation of oral clearance to common environmental effects influencing both siblings to the same extent and 46.5 % to unique environmental effects randomly affecting individual subjects. Talinolol pharmacokinetics were significantly dependent on sex, body mass index, total protein consumption, and vegetable consumption.
The twin study revealed that environmental factors explained much more of the variation in pharmacokinetics of talinolol than genetic factors.
European clinical trials database number: EUDRA-CT 2008-006223-31. Registered 26 September 2008. ClinicalTrials.gov number: NCT01845194 .

ATP-binding cassette (ABC) transporters have been associated with methylmercury (MeHg) toxicity in experimental animal models.
To evaluate the association of single nucleotide polymorphisms (SNPs) in maternal ABC transporter genes with 1) maternal hair MeHg concentrations during pregnancy and 2) child neurodevelopmental outcomes.
Nutrition Cohort 2 (NC2) is an observational mother-child cohort recruited in the Republic of Seychelles from 2008-2011. Total mercury (Hg) was measured in maternal hair growing during pregnancy as a biomarker for prenatal MeHg exposure (N=1313) (mean 3.9ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20months of age (N=1331). Genotyping for fifteen SNPs in ABCC1, ABCC2 and ABCB1 was performed for the mothers.
Seven of fifteen ABC SNPs (ABCC1 rs11075290, rs212093, and rs215088; ABCC2 rs717620; ABCB1 rs10276499, rs1202169, and rs2032582) were associated with concentrations of maternal hair Hg (p<0.001 to 0.013). One SNP (ABCC1 rs11075290) was also significantly associated with neurodevelopment; children born to mothers with rs11075290 CC genotype (mean hair Hg 3.6ppm) scored on average 2 points lower on the Mental Development Index (MDI) and 3 points lower on the Psychomotor Development Index (PDI) than children born to mothers with TT genotype (mean hair Hg 4.7ppm) while children with the CT genotype (mean hair Hg 4.0ppm) had intermediate BSID scores.
Genetic variation in ABC transporter genes was associated with maternal hair Hg concentrations. The implications for MeHg dose in the developing child and neurodevelopmental outcomes need to be further investigated.

P-glycoprotein, encoded by the ABCB1 gene, functions as an ATP-driven efflux pump in the blood-brain barrier, extruding its substrates and thereby limiting their passage into the brain. ABCB1 polymorphisms predicted antidepressant drug response: Minor allele carriers of SNPs rs2032583 and rs2235015 had higher remission rates than major allele homozygotes. The aim of the current study was to evaluate an ABCB1 genotype-dependent efficacy of a quick dose escalation strategy. Depressed inpatients (n = 73) treated with antidepressants that are P-glycoprotein substrates were randomly assigned to a standard or high dose condition for 28 days. HAM-D scores, adverse effects and plasma antidepressant concentration were measured weekly and tested among two intronic SNPs rs2032583 and rs2235015. A treatment as usual control sample (n = 128) was retrospectively matched to the study group by gender, age, and diagnosis. There was a significant interaction of genotype x plasma antidepressant concentration: Minor allele carriers of rs2032583 [F(1,65) = 7.221, p = 0.009] and rs2235015 [F(1,65) = 4.939, p = 0.030] whose plasma drug concentration were within recommended range had a greater symptom reduction at study endpoint which exceeded the therapeutic benefit of the treatment as usual group [for rs2032583: F(1,163) = 4.366, p = 0.038]. Minor allele carriers of rs2032583 with high plasma drug levels had more sleep-related side effects than major allele homozygotes with high plasma drug levels. The treatment of MDD can be optimized by ABCB1 genotyping combined with monitoring of plasma drug concentrations: For minor allele carriers of rs2032583 and rs2235015, plasma antidepressant levels should not exceed the recommended range in order to obtain optimal treatment outcome.