Solute Carrier Organic Anion Transporter 1B1 Research Articles

Evaluation of bleeding and anticoagulation markers by edoxaban and low-dose cyclosporine: A case series study.

It was reported that high-dose cyclosporine at 500mg daily increases edoxaban exposure. We investigated whether cyclosporine <500mg daily leads to edoxaban-induced bleeding in the clinical setting. This case series study included patients receiving edoxaban and cyclosporine at Mie University Hospital. The outcomes were bleeding and anticoagulant markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and the international normalized ratio of prothrombin time (PT-INR). We examined the genotypes of cytochrome P450 3A5 (CYP3A5), multidrug resistance 1 (ABCB1), and solute carrier organic anion transporter 1B1 (SLCO1B1). Trends in anticoagulant markers were analyzed. Thirteen patients received edoxaban (standard dose; n=3 and reduced dose; n=10) and cyclosporine (1.94±1.42mg/kg). A bleeding event occurred in one patient receiving a standard dose of edoxaban plus cyclosporine of 25mg daily (HAS-BLED score of 2 and genotypes; CYP3A5*3/*3, ABCB1 3435CT, and SLCO1B1*1a/*1b). After edoxaban treatment, anticoagulant markers were prolonged (APTT; 27.95±3.64s vs. 31.11±3.90s, p<0.001, PT; 11.53±1.01s vs. 13.03±0.98s, p=0.002, PT-INR; 0.98±0.09 vs. 1.11±0.11, p=0.007). In summary, the genotypes of CYP3A5, ABCB1, and SLCO1B1 and the dosage of edoxaban may affect the risk of bleeding by edoxaban when co-administered with cyclosporine, even at low doses.

Impact of SLCO1B1*5 on Flucloxacillin and Co-Amoxiclav-Related Liver Injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is a serious uncommon disease that may develop as a result of the intake of certain drugs such as the antimicrobials flucloxacillin and co-amoxiclav. The reported cases showed significant associations between DILI and various human leukocyte (HLA) markers. The solute carrier organic anion transporter 1B1 (SLCO1B1), a non-HLA candidate gene, was previously reported as a risk factor for liver injury induced by rifampin and methimazole. This study presumed that SLCO1B1 may play a general role in the DILI susceptibility and therefore investigated the association of rs4149056 (SLCO1B1*5, T521C) polymorphism with flucloxacillin- and co-amoxiclav–induced liver injury. Methodology: We recruited 155 and 165 DILI cases of white ancestral origin from various European countries but mainly from the United Kingdom owing to flucloxacillin and co-amoxiclav, respectively. Only adult patients (≥18 years) who were diagnosed with liver injury and who showed i) clinical jaundice or bilirubin >2x the upper limit of normal (ULN), ii) alanine aminotransferase (ALT) >5x ULN or iii) alkaline phosphatase (ALP) >2x ULN and bilirubin > ULN were selected. The population reference sample (POPRES), a European control group (n = 282), was used in comparison with the investigated cases. TaqMan SNP genotyping custom assay designed by Applied Biosystems was used to genotype both DILI cohorts for SLCO1B1 polymorphism (rs4149056). Allelic discrimination analysis was performed using a step one real-time PCR machine. Genotype differences between cases and controls were examined using Fisher’s exact test. GraphPad Prism version 5.0 was used to determine the p-value, odds ratio, and 95% confidence interval. Compliance of the control group with Hardy–Weinberg equilibrium was proven using a web-based calculator available at https://wpcalc.com/en/equilibrium-hardy-weinberg/. Results: A small number of cases failed genotyping in each cohort. Thus, only 149 flucloxacillin and 162 co-amoxiclav DILI cases were analyzed. Genotyping of both DILI cohorts did not show evidence of association with the variant rs4149056 (T521C) (OR = 0.71, 95% CI = 0.46–1.12; p = 0.17 for flucloxacillin cases and OR = 0.87, 95% CI = 0.56–1.33; p = 0.58 for co-amoxiclav), although slightly lower frequency (22.8%) of positive flucloxacillin cases was noticed than that of POPRES controls (29.4%). Conclusion: Carriage of the examined allele SLCO1B1*5 is not considered a risk factor for flucloxacillin DILI or co-amoxiclav DILI as presumed. Testing a different allele (SLCO1B1*1B) and another family member gene (SLCO1B3) may still be needed to provide a clearer role of SLCO1B drug transporters in DILI development–related to the chosen antimicrobials.

Association between SLCO1B1 polymorphism and methotrexate-induced hepatotoxicity: a systematic review and meta-analysis.

Reports on the association between the solute carrier organic anion transporter 1B1 (SLCO1B1) T521C polymorphism and methotrexate-induced hepatotoxicity in patients with malignancies are inconsistent. This meta-analysis evaluated the association between the SLCO1B1 T521C polymorphism and methotrexate-induced hepatotoxicity. We performed a systematic review of previous reports from the PubMed, Web of Science, and EMBASE databases, and a meta-analysis was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the effect of the SLCO1B1 T521C polymorphism on the occurrence of methotrexate-induced hepatotoxicity. In total, data from five studies including 465 patients were analyzed. Patients had received a high-dose methotrexate regimen (1-5 g/m2). The SLCO1B1 variant allele (C allele) carriers had a 1.9-fold higher risk of hepatotoxicity than wild-type homozygote carriers (TT; OR, 1.94; 95% CI, 1.14-3.31). This meta-analysis demonstrated that C allele carriers of the SLCO1B1 polymorphism had a higher risk of hepatotoxicity than patients with the TT genotype. The SLCO1B1 T521C polymorphism may be a useful predictor for methotrexate-induced hepatotoxicity in patients with malignancies.

SLCO1B1 Gene Polymorphisms (rs2306283 and rs4149056) and Statin-Induced Myopathy in Jordanian Diabetics.

The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

Utilidad del gen SLCO1B1 como marcador de interés en la farmacogenómica de las estatinas

Cardiovascular diseases are the main cause of death in the world. Lipid-lowering drugs like statins are the first alternative in the primary prevention of cardiovascular events, strokes, and revascularisation procedures. These drugs are HMG-CoA reductase inhibitors, which regulate the rate of cholesterol synthesis, as well as increase its liver uptake via the LDL receptor pathway. The organic anion transporter polypeptide 1B1 (OATP1B1) coded by the solute carrier organic anion transporter 1B1 (SLCO1B1) gene is one of the hepatic influx and efflux transporters of statins. In genome-wide association studies (GWAS) different single nucleotide polymorphisms (SNPs) have been reported within the SLCO1B1 gene that are able to reduce the statin uptake mediated by OATP1B1. This suggests that the variations in the sequencing of this gene have an influence on the pharmacokinetics and pharmacodynamics of these drugs, leading to a condition known as statin-induced myopathy. Genes that affect cardiovascular treatments, as well as the current advances in diagnostic tests based on their sequencing, now offer the possibility of revolutionising their diagnosis and treatment. They could be used with the aim of validating risk prediction, prognosis, prevention, and management of patients with a risk of cardiovascular diseases, and will lead to the development of new forms of medical treatments.

Effect of SLCO1B1 gene polymorphisms and vitamin D on statin-induced myopathy.

Background Statin therapy used to lower cholesterol levels results in a substantial reduction in cardiovascular complications. Previous observations in different ethnic populations showed that rs2306283A>G, p.Asn130Asp and rs4149056T>C, p.Val174Ala in solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the organic transporter protein may be responsible for statin uptake, thus explaining the majority of statin-associated symptoms. In addition to the genetic component, vitamin D (vit D) deficiency is common in Saudi Arabia and worldwide and may cause muscle dysfunction and ache. The aim of the present study was first to reveal an effect of vit D, rs2306283A>G, and rs4149056T>C and related haplotypes on statin-associated myopathy (SAM) and then to investigate a possible interaction between low vit D levels and the above-mentioned variants. Methods The genomic DNA obtained from 50 individuals diagnosed with hypercholesterolemia was genotyped using light SNiP hybridization probes. Results Low vit D levels were associated with SAM (OR=3.6, p=0.03); however, CK levels, rs2306283A>G, and rs4149056T>C did not show any association. Interestingly, rs4149056T>C was interacting with vit D to influence SAM (p=0.02). Haplotype analysis showed that SLCO1B1 *1B and *15 were more prevalent in individuals with SAM (p=0.05). When stratified according to vit D levels, rs2306283A allele showed an increase in individuals having SAM along with low vit D (p=0.03). Conclusions Although preliminary, our results show an involvement of vit D and rs4149056T>C of SLCO1B1 in SAM.

Influence of SLCO1B1 polymorphisms on atorvastatin efficacy and safety in Macedonian subjects.

Atorvastatin, as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a widely prescribed medication for the treatment of dyslipidemia. However, despite its clinical efficacy in reducing major cardiovascular events, a wide inter-individual variability in its response exists. Several studies in this area point to the effect of polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the multiple organic anion-transporting polypeptide 1B1 (OATP1B1) involved in hepatic uptake of atorvastatin. Hence, the aim of this study was to analyze the association between the SLCO1B1 c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G polymorphisms and lipid-lowering effect and safety of atorvastatin. A hundred and fifty six patients with hyperlipidemia IIa and IIb, all of Macedonian origin, were included in the study receiving atorvastatin 20 - 80 mg/day for 3 months. SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped using the TaqMan allelic discrimination assay. As parameters of atorvastatin response, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein A (ApoAI), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), creatine phosphokinase (CPK), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, using standard laboratory methods, at baseline and after 3 months of treatment. No statistically significant association between the different SLCO1B1 SNPs and atorvastatin response was observed. However, the carriers of c.521CC manifested a lower decrease in plasma levels of TG, TC, LDL-C and Lp(a), with percentage difference being 16%, 7%, 29% and 149%, respectively, compared to the carriers of c.521TT variant. Lower increase in HDL-C (271%) and ApoAI (293%) and higher increase in CPK (69%) in c.521CC carriers were also observed, confirming the lower OATP1B1 activity in carriers of the variant c.521 C allele. Similar results were obtained when a comparison between the percentage of biochemical parameter change was made between *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers. The lack of a statistically significant association between the SLCO1B1 polymorphism and atorvastatin response can be explained dominantly by the low number of individuals homozygous for the rare c.521C variant allele. Despite this limitation, the study offers valuable information on the influence of the genetic determinant SLCO1B1 on atorvastatin response in the Macedonian population.

Effect of genetic variants of bilirubin metabolism on the degree of hyperbilirubinemia in African-American newborns.

The objective of our study was to measure the effect of genetic variants of these two enzymes, UGT1A1 and SLCO1B1, in the bilirubin metabolic pathway on the degree of hyperbilirubinemia in a cohort of African-American (AA) infants from our well-baby nursery. In addition, a second objective was to document the types and frequencies of genetic variations of these enzymes in our cohort. A prospective study of 180 AA infants from the Well Baby Nursery of an inner city community hospital, all of whose mothers were type O pos. Sixty infants were ABO-incompatible direct antiglobulin test (DAT) pos, 60 were ABO-incompatible DAT neg and 60 were type O+. Blood for carboxyhemoglobin (COHb) and variants of the enzymes uridine diphosphoglucuronosyltransferase 1A1 and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) was drawn at the time of the infants' initial bilirubin, and the infants' precise percentile on the Bhutani nomogram was calculated. Variants in the two enzymes studied were quite common. In total, 21.1% were positive for a Gilbert phenotype, whereas an additional 42.4% were heterozygous for the *28 or *37 variant of UGT1A1. In total, 67.2% were homozygous for the *60 variant of the phenobarbital responsive enhancer module. In total, 41.1% were homozygous for the *1b variant of SLCO1B1, whereas an additional 12.7% were positive for the *4 variant of this gene. In total, 20.6% of infants had variations in both genes. Using logistic regression when COHbc was assessed with each of the different variants, only COHbc (P<0.0001 to 0.0004) was significantly associated with the level of hyperbilirubinemia as defined by the Bhutani nomogram. Although we have found quite a large number of genetic variants of the UGT1A1 and SLCO1B1 genes in the AA population, it does not appear that they have a significant impact on the incidence of hyperbilirubinemia among this group of infants.

Predictors of Delayed Clearance and Toxicities from High Dose Methotrexate in Patients Receiving Hypercvad Regimen for Treatment of Lymphoid Malignancies

Introduction: High dose Methotrexate (HDMTX) has been the backbone of chemotherapeutic regimens used for the treatment of lymphoid malignancies. Altered disposition of MTX may result in increased systemic exposure accompanied by severe adverse effects and organ toxicities. Diversity in toxicity profile has been shown to be associated with various clinical factors as well as genetic polymorphisms. In particular, single nucleotide polymorphisms (SNPs) in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene especially rs4149056 and rs2306283 had been previously reported to be significantly associated with MTX concentration at 24 hours post-infusion, MTX AUC from 0-48 hours, MTX clearance and toxicities in the Caucasian pediatric population.Aim: This study aimed to characterize clearance and toxicity profile [in particular acute kidney injury (AKI) and hepatotoxicity]; and identify clinical and genetic covariates associated with clearance and toxicities of HDMTX in patients receiving HyperCVAD-B regimen for treatment of lymphoid malignancies in the local setting.Methods: This single-centered, retrospective study included all treatment-naïve patients of Asian descent who received HDMTX as part of the HyperCVAD-B regimen for treatment of lymphoid malignancies from January 2008 to December 2015 in Department of Hematology, Singapore General Hospital. Pertinent clinical data including baseline demographics, disease characteristics, treatment details, plasma MTX levels, and treatment outcomes were extracted from case notes and electronic records onto a standardized data collection form. Association between toxicities parameters and MTX levels were analyzed. Genotyping for two SNPs in the SLCO1B1 gene namely, rs2306283 and rs4146056 was using blood samples obtained from the Hematology Department Tissue Repository. Primary endpoint was incidence of delayed clearance and toxicities of HDMTX in the study population. Secondary endpoints included clinical factors and genetic covariates associated with reduced MTX clearance and toxicities.Results: A total of 102 patients (215 treatment cycles) were included, with each patient receiving median of 2 cycles (range, 1 to 6). Median age was 45 years (range, 18 - 69), and 58 (56.9%) were male. Eighty-seven patients were diagnosed with acute lymphoblastic leukemia (ALL), whereas 12 patients had lymphoma. Sixty-one patients (59.8%) were found to have at least 1 episode of delayed clearance, occurring in 89 (41.4%) treatment cycles. Median time to MTX clearance was significantly longer in patients with delayed clearance at 69.8 hours (range, 4.5-277.2) as compared to 41 hours (range, 0 - 86.3 hours), p<0.001. Approximately 25% and 47% of the patients developed AKI and hepatotoxicity attributable to MTX, respectively. A significant association between delayed clearance and occurrence of AKI was observed, with 24% of patients with delayed clearance developing AKI vs 2% in those without delayed clearance, p<0.001. Number of treatment cycles [odds ratio (OR) = 2, 95% confidence interval (CI) 1.3 - 3.1, p = 0.002]; and age ≥ 40 (OR 3.7, 95% CI 1.4 - 9.6, p = 0.008) were found to be associated with delayed clearance. Occurrence of delayed clearance (OR = 29, 95% CI = 3.7 - 228, p = 0.001), and baseline hepatic impairment (OR = 9.5, 95% CI = 2 - 45, p = 0.005) were found to predict for AKI and hepatotoxicity, respectively. Genotyping for SLCO1B1 rs2306283 and rs4146056 was carried out for 39 patients with samples available in the repository. Frequencies and outcomes were shown in Table 1 and Table 2, respectively. Due to the small sample size, no definitive correlations between specific genotypes and clearance and outcomes could be elucidated.Conclusion: Delayed clearance of HDMTX occurred in a substantial proportion of patients at approximately 60%, which was in turn associated with occurrence of AKI. Risk of delayed clearance seemed to increase with age (≥ 40) and number of treatment cycles. This underscores the need for more effective strategies to facilitate clearance of HDMTX especially in patients with identified risk factors. Larger sample size would be essential to determine associations between genotypes and clearance and toxicities. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Association Between SLCO1B1 Gene T521C Polymorphism and Statin-Related Myopathy Risk: A Meta-Analysis of Case-Control Studies.

Statin-related myopathy is an important adverse effect of statin which is classically unpredictable. The evidence of association between solute carrier organic anion transporter 1B1 (SLCO1B1) gene T521C polymorphism and statin-related myopathy risk remained controversial. This study aimed to investigate this genetic association. Databases of PubMed, EMBASE, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database, and Wanfang Data were searched till June 17, 2015. Case-control studies investigating the association between SLCO1B1 gene T521C polymorphism and statin-related myopathy risk were included. The Newcastle-Ottawa Scale (NOS) was used for assessing the quality of included studies. Data were pooled by odds ratios (ORs) and their 95% confidence intervals (CIs). Nine studies with 1360 cases and 3082 controls were included. Cases of statin-related myopathy were found to be significantly associated with the variant C allele (TC + CC vs TT: OR = 2.09, 95% CI = 1.27-3.43, P = 0.003; C vs T: OR = 2.10, 95% CI = 1.43-3.09, P < 0.001), especially when statin-related myopathy was defined as an elevation of creatine kinase (CK) >10 times the upper limit of normal (ULN) or rhabdomyolysis (TC + CC vs TT: OR = 3.83, 95% CI = 1.41-10.39, P = 0.008; C vs T: OR = 2.94, 95% CI = 1.47-5.89, P = 0.002). When stratified by statin type, the association was significant in individuals receiving simvastatin (TC + CC vs TT: OR = 3.09, 95% CI = 1.64-5.85, P = 0.001; C vs T: OR = 3.00, 95% CI = 1.38-6.49, P = 0.005), but not in those receiving atorvastatin (TC + CC vs TT: OR = 1.31, 95% CI = 0.74-2.30, P = 0.35; C vs T: OR = 1.33, 95% CI = 0.57-3.12, P = 0.52). The available evidence suggests that SLCO1B1 gene T521C polymorphism is associated with an increased risk of statin-related myopathy, especially in individuals receiving simvastatin. Thus, a genetic test before initiation of statins may be meaningful for personalizing the treatment.

Association of ABCB1, ABCC2 and SLCO1B1 gene polymorphisms with toxicity response of high dose methotrexate chemotherapy

Objective To investigate the association between single nucleotide polymorphisms (SNPs) of ATP-binding cassette B1 (ABCB1), ATP-binding cassette C2 (ABCC2) and solute carrier organic anion transporter 1B1 (SLCO1B1) genes with high dose methotrexate (HDMTX)-induced toxicity in children with acute lymphoblastic leukemia(ALL). Methods This study was designed as a case-control.From September of 2005 to December of 2011，the blood samples were randomly collected from 142 ALL patients from Nanjing Children′s Hospital, Enzyme-multiplied immunoassay technique (EMIT) was used to measure the plasma concentration of MTX, Seven SNPs in ABCB1 (rs1045642,rs2032582,rs1128503), ABCC2 (rs717620,rs2273697) and SLCO1B1 (rs4149081,rs11045879) genes were detected by polymerase chain reaction-ligase detection reaction (PCR-LDR). Results A significantly increased risk of MTX-induced toxicity was observed in patients with MTX elimination delay （OR=2.828, 95%CI:1.217-6.571，P<0.05).Two SNPs in SLCO1B1, rs4149081 and rs11045879 were linkage disequilibrium (LD) with each other （R2=0.979, P<0.05）.Multivariate analysis revealed that individuals with SLCO1B1 rs4149081 AA genotype or SLCO1B1 rs11045879 CC genotype showed increased incidence of MTX elimination delay （OR=4.41, 95%CI:1.537-12.654, P=0.042）, and the two genotypes were also associated with significantly increased risk of MTX-induced toxicity （OR=4.118, 95%CI:1.135-14.944, P=0.022）.No association of MTX elimination delay or MTX-induced toxicity with the other SNPs analyzed was found. Conclusions SLCO1B1 rs4149081 AA or SLCO1B1 rs11045879 CC genotypes might be a risk factor for the susceptibility to MTX-induced toxicity in children with ALL.(Chin J Lab Med, 2014,37:60-65) Key words: Organic anion transporters; Methotrexate; Precursor cell lymphoblastic leukemia-lymphoma; P-Glycoprotein; Multidrug resistance-associated proteins; Polymorphism, single nucleotide

Identifying term breast-fed infants at risk of significant hyperbilirubinemia

The aim of this study was to establish a model to identify term breast-fed infants who are at risk of developing significant neonatal hyperbilirubinemia. A prospective study was designed to investigate the effects of birth weight, mode of delivery, cephalohematoma, glucose-6-phosphate dehydrogenase (G6PD) deficiency, predischarge total serum bilirubin, variant uridine 5'diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on significant hyperbilirubinemia in term breast-fed neonates. Significant hyperbilirubinemia was defined as a bilirubin level exceeding the hour-specific phototherapy treatment threshold recommended by the American Academy of Pediatrics in 2004. Of 240 exclusively breast-fed term neonates, 26 (10.8%) had significant hyperbilirubinemia. The predischarge total serum bilirubin on the third day (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.87-3.70; P < 0.001) and the variant UGT1A1 gene at nucleotide 211 (OR = 5.00; 95% CI: 1.08-23.03; P < 0.05) were significant risk factors. The area under the receiver operating characteristic (ROC) curve of the predictive probability was 0.964 (95% CI: 0.932-0.984; P < 0.0001). Combining the total serum bilirubin on the third day and the variant UGT1A1 gene at nucleotide 211 can predict hyperbilirubinemia well in term breast-fed infants.

Do MDR1 and SLCO1B1 Polymorphisms Influence the Therapeutic Response to Atorvastatin? A Study on a Cohort of Egyptian Patients with Hypercholesterolemia

Statins are among the most prescribed drugs worldwide to reduce the risk of cardiovascular events. Interindividual variability in drug response is a major clinical problem and is of concern during drug development. Statins, such as atorvastatin, are taken orally and access to their site of action in the liver is greatly facilitated by both intestinal and hepatic transporters. To examine the impact of polymorphisms of the multidrug resistance 1(MDR1) and solute carrier organic anion transporter 1B1 (SLCO1B1) genes on the therapeutic response to atorvastatin as well as the presence of gender-gene interaction. Serum lipid levels were determined at baseline and 4weeks following 40mg/day atorvastatin treatment in 50 Egyptian hypercholesterolemic patients (27 males and 23 females). Identification of MDR1 C3435T and SLCO1B1 A388G gene polymorphisms was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Treatment with atorvastatin resulted in a mean reduction of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) of 8.7%, 9.2%, and 4.1%, respectively, and a mean increase of high density lipoprotein cholesterol (HDL-C) of 1%. Baseline and post-treatment HDL-C levels were statistically significantly higher in the MDR 1 TT homozygotes when compared with the CC wild type. The percentage change in TC, LDL-C, TG, and HDL-C did not show any statistically significant difference when compared among the different MDR 1 C3435T or SLCO1B1 A388G genotypes. The SLCO1B1 GG homozygotes showed a decrease in TG, whereas there was an increase in TG following atorvastatin treatment in AA and AG carriers in females; however, males did not show any statistically significant difference. There was no statistically significant association between either the coronary artery disease (CAD) risk factors (family history of CAD, hypertension, diabetes mellitus, smoking) or concomitant medications with the percentage change in different lipid parameters. MDR1 C3435T was associated with baseline and post-treatment HDL-C variation. SLCO1B1 A388G showed gender-related effects on TG change following atorvastatin treatment. None of the comorbidities or the concomitant medications influenced the percentage change of lipid parameters following atorvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipid response to atorvastatin treatment.

Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders

Cardiovascular disease is a leading cause of death worldwide. Many pharmacologic therapies are available that aim to reduce the risk of cardiovascular disease but there is significant inter-individual variation in drug response, including both efficacy and toxicity. Pharmacogenetics aims to personalize medication choice and dosage to ensure that maximum clinical benefit is achieved whilst side effects are minimized. Over the past decade, our knowledge of pharmacogenetics in cardiovascular therapies has increased significantly. The anticoagulant warfarin represents the most advanced application of pharmacogenetics in cardiovascular medicine. Prospective randomized clinical trials are currently underway utilizing dosing algorithms that incorporate genetic polymorphisms in cytochrome P450 (CYP)2C9 and vitamin k epoxide reductase (VKORC1) to determine warfarin dosages. Polymorphisms in CYP2C9 and VKORC1 account for approximately 40% of the variance in warfarin dose. There is currently significant controversy with regards to pharmacogenetic testing in anti-platelet therapy. Inhibition of platelet aggregation by aspirin in vitro has been associated with polymorphisms in the cyclo-oxygenase (COX)-1 gene. However, COX-1 polymorphisms did not affect clinical outcomes in patients prescribed aspirin therapy. Similarly, CYP2C19 polymorphisms have been associated with clopidogrel resistance in vitro, and have shown an association with stent thrombosis, but not with other cardiovascular outcomes in a consistent manner. Response to statins has been associated with polymorphisms in the cholesterol ester transfer protein (CETP), apolipoprotein E (APOE), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, calmin (CLMN) and apolipoprotein-CI (APOC1) genes. Although these genes contribute to the variation in lipid levels during statin therapy, their effects on cardiovascular outcomes requires further investigation. Polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene is associated with increased statin exposure and simvastatin-induced myopathy. Angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists (β-blockers) are medications that are important in the management of hypertension and heart failure. Insertion and deletion polymorphisms in the ACE gene are associated with elevated and reduced serum levels of ACE, respectively. No significant association was reported between the polymorphism and blood pressure reduction in patients treated with perindopril. However, a pharmacogenetic score incorporating single nucleotide polymorphisms (SNPs) in the bradykinin type 1 receptor gene and angiotensin-II type I receptor gene predicted those most likely to benefit and suffer harm from perindopril therapy. Pharmacogenetic studies into β-blocker therapy have focused on variations in the β1-adrenoceptor gene and CYP2D6, but results have been inconsistent. Pharmacogenetic testing for ACE inhibitor and β-blocker therapy is not currently used in clinical practice. Despite extensive research, no pharmacogenetic tests are currently in clinical practice for cardiovascular medicines. Much of the research remains in the discovery phase, with researchers struggling to demonstrate clinical utility and validity. This is a problem seen in many areas of therapeutics and is because of many factors, including poor study design, inadequate sample sizes, lack of replication, and heterogeneity amongst patient populations and phenotypes. In order to progress pharmacogenetics in cardiovascular therapies, researchers need to utilize next-generation sequencing technologies, develop clear phenotype definitions and engage in multi-center collaborations, not only to obtain larger sample sizes but to replicate associations and confirm results across different ethnic groups.

Association of Liver Stiffness with Hepatic Expression of Pharmacokinetically Important Genes in Alcoholic Liver Disease

Enhanced drug elimination in alcoholics remains largely indefinable. In contrast, the reduced elimination of drugs in patients with advanced alcoholic liver disease (ALD) is normally owing to hepatic end-stage disease such as cirrhosis. We here study the mRNA expression of various hepatic drug metabolizing enzymes and transporters in association with liver stiffness (LS) being a novel noninvasive parameter for the assessment of cirrhosis to unravel the dynamic relationship between ALD and determinants of pharmacokinetics such as drug metabolizing enzymes and transporters. We quantified mRNA expression levels of various cytochrome P-450 isoenzymes (CYPs) and drug transporters in 26 liver specimens of chronic alcoholics and 5 controls by quantitative polymerase chain reaction. In addition, liver histology, clinical data, and LS evaluated by transient elastography (Fibroscan) were obtained. Eighteen patients had a normal or moderate LS < 8 kPa (69.2%), while in the remaining 8 patients (30.7%) advanced F3 or F4 fibrosis could be established with an LS > 8 kPa. Overall, CYP3A4, CYP2E1, and solute carrier organic anion transporter 1B1 (SLCO1B1) were negatively correlated with increasing LS. CYPs and drug transporters tended to be up-regulated in alcoholics without advanced fibrosis (LS < 8.0 kPa) compared to healthy controls supporting data of boosted drug elimination in alcoholics without advanced ALD. However, in alcoholics with severely increased LS (>8 kPa), expression levels of CYP2E1, SLC22A2, and SLCO1B1 were significantly lower. In conclusion, CYPs and drug transporters seem to be induced in chronic alcoholics without irreversible liver damage but decline in case of manifest cirrhosis. Our study also suggests that noninvasive measurements of LS could be useful for pharmacokinetic predictions and individualized pharmacotherapy.

Risk of Hyperbilirubinemia in Breast-Fed Infants

To investigate the risk factors for hyperbilirubinemia in infants who are exclusively breast-fed. A prospective study was conducted to investigate the effects of birth body weight, sex, mode of delivery, glucose-6-phosphate dehydrogenase (G6PD) deficiency, variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on hyperbilirubinemia in neonates who were breast-fed. Hyperbilirubinemia was diagnosed when a full term neonate had a bilirubin level ≧15.0 mg/dL (256.5 μM) in serum at 3 days old. The polymerase chain reaction-restriction fragment length polymorphism method was used as a means of detecting the known variant sites in the UGT1A1 and SLCO1B1 gene. Of 252 infants born at term who were exclusively breast-fed, 59 (23.4%) had hyperbilirubinemia. The significant risk factors were a variant nucleotide 211 in UGT1A1 (2.48; 95% CI, 1.29 to 4.76; P = .006), G6PD deficiency (12.24; 95% CI, 1.08 to 138.62; P < .05), and vaginal delivery (3.55; 95% CI, 1.64 to 7.66; P < .001). Breast-fed neonates who are 211 variants in the UGT1A1, G6PD deficiency, and vaginal delivery are at high-risk for hyperbilirubinemia.

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. Despite this, there is wide inter-individual variability in response to statin therapy, in terms of both lipid-lowering and adverse drug reactions. The major site of statin action is within hepatocytes and recent interest has focussed on genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. In this review we explore current literature regarding the pharmacokinetic and pharmacodynamic influence of the common c.388A>G and c.521T>C single-nucleotide polymorphisms (SNPs) within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their potential to predict the efficacy of statin therapy and the likelihood that patients will experience adverse effects.

Complex Multifactorial Nature of Significant Hyperbilirubinemia in Neonates

To determine whether glucose-6-phosphate dehydrogenase (G6PD), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1), and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene variants occur at greater frequency in neonates with significant hyperbilirubinemia. Infants with gestational ages of >or=37 weeks and ages of <7 days were studied. Case subjects had >or=1 bilirubin level above the 95th percentile (high-risk zone), whereas control subjects had bilirubin levels of <40th percentile (low-risk zone) at study entry. A total of 153 case subjects (median bilirubin level: 15.7 mg/dL) and 299 control subjects (median bilirubin level: 4.6 mg/dL) were evaluated. There were no statistical differences in the frequencies of G6PD, UGT1A1, and SCLO1B1 gene variants between case and control subjects (G6PD: 5.2% vs 3.3%; UGT1A1: 14.4% vs 9.4%; SLCO1B1: 73.2% vs 73.6%). However, coexpression of the G6PD African A- mutation with UGT1A1 and/or SLCO1B1 variants was seen more frequently for case subjects. Case subjects more often demonstrated >or=2 factors contributing to hyperbilirubinemia, including ABO blood group heterospecificity in which the mother had blood group O (47.7% vs 11.4%), positive direct Coombs test results (33.3% vs 4%), sibling treated with phototherapy (16.3% vs 5.4%), maternal circulating blood group antibodies (10.5 vs 0.7%), maternal diabetes mellitus (13.1% vs 6.4%), and maternal East Asian ethnicity (6.5% vs 1.3%). Clinical contributors to hyperbilirubinemia were identified more frequently for case subjects but individually G6PD, UGT1A1, and SLCO1B1 variants were not. Coexpression of the G6PD African A- mutation with UGT1A1 and SLCO1B1 variants was seen more often for case subjects.