Pharmacogenetic analysis of inter-ethnic variability in the uptake transporter SLCO1B1 gene in Colombian, Mozambican, and Portuguese populations.

BACKGROUND: Statin-induced myopathy is reported to be associated with the solute carrier organic anion transporter family member 1B1 gene single nucleotide polymorphism, c.521 T > C. There is no epidemiologic data on this gene polymorphism in several countries. Therefore, this study aimed at assessing the genotype and allele frequencies of the gene variant in three countries. METHODS: This study involved healthy individuals from Colombia, Mozambique, and Portugal. Genomic DNA was isolated from blood samples using the Qiamp DNA Extraction Kit (Qiagen). The isolated DNA was genotyped using novel Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. Microstat and GraphPad QuickCal software were used for the Chi-square test and the evaluation of Hardy-Weinberg equilibrium respectively. RESULTS: A total of 181 individuals' blood samples were analyzed. Overall, the TT (74.0%) genotype was the highest and the CC (7.8%) was the lowest. Country wise genotypic frequencies were Colombia 47(70.2%) TT, 12(17.9%) TC and 8(11.9%) CC; Mozambique 47(88.7%) TT, 5(9.4%) TC, and 1(1.9%) CC; and Portugal 40(65.6%) TT, 16(26.2%) TC, and 5(8.2%) CC. The reference (T) allele was highest among Mozambicans (93.4%) compared to Colombians (79.1%) and Portuguese (78.7%). Mozambicans showed statistically significant genotypic and allelic frequency differences compared to Colombians (p < 0.01) and Portuguese (p < 0.01). CONCLUSIONS: Overall and country-wise, CC genotype was less frequent and it is relatively high for Colombians and Portuguese populations. This finding may imply statins risk-benefit variability associated with CC genotype among these populations that needs further understanding.

P-Glycoprotein and Organic Anion Transporter Polypeptide 1B/Breast Cancer Resistance Protein Drug Transporter Activity in Pregnant Women Living With HIV.

This study evaluates the influence of pregnancy and HIV infection in conjunction with the use of raltegravir, lamivudine, and tenofovir disoproxil fumarate (combined antiretroviral therapy [cART]) on intestinal P-glycoprotein (P-gp) and hepatic organic anion transporter polypeptide (OATP) 1B1/1B3 and/or breast cancer resistance protein (BCRP) drug transporter activity using rosuvastatin (OATP1B/BCRP) and fexofenadine (P-gp) probes. Single oral doses of 5-mg rosuvastatin and 60-mg fexofenadine were administered to women living with HIV under cART in the third trimester of gestation (n = 15) and postpartum period (n = 10). A control group of 12 healthy nonpregnant women also was investigated. Pharmacokinetic parameters were estimated by using a noncompartmental method and evaluated by t test (P < .05). The rosuvastatin area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last ) value was higher in the third trimester of pregnancy (19.5 [95%CI, 16.8-22.3] ng • h/mL] when compared to postpartum (13.3 [95%CI, 9.3-17.5] ng • h/mL), while the fexofenadine AUC0-last values did not differ between the third trimester of pregnancy (738.0 [95%CI, 611.4-864.6] ng • h/mL) and postpartum period (874.9 [95%CI, 408.2-1342.0] ng• h/mL). The rosuvastatin AUC0-last values did not differ between healthy nonpregnant women (13.8 [95%CI, 10.0-17.6] ng • h/mL) and women living with HIV in the postpartum period (13.3 [95%CI, 9.3-17.5] ng • h/mL), and the fexofenadine AUC0-last values did not differ between the 2 investigated groups (603.6 [95%CI, 467.5-739.7] ng • h/mL vs 874.9 [95%CI, 408.2-1342.0] ng • h/mL). It is suggested that gestation inhibits the hepatic OATP1B1/1B3 and/or BCRP activity but does not alter intestinal P-gp activity. The influence of HIV infection in conjunction with use of cART on OATP1B/BCRP and intestinal P-gp activity was not observed.

SLCO1B1 and SLC10A1 polymorphism and plasma rifampin concentrations in patients with co-morbidity tuberculosis-diabetes mellitus in Baja California, Mexico.

Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin Cmax. TB and T2DM patients with suboptimal Cmax rifampicin levels showed wild alleles in rs11045819 and rs2291075 in SLCO1B1 SLC10A1 and SLC10A1. This is the first study to analyze SLC10A1 and SLCO1B1 polymorphisms in TB and TB-T2DM patients and healthy individuals in Mexico. Further research to confirm and extend these findings is necessary.

Pharmacogenetics of taxane-induced neurotoxicity in breast cancer: Systematic review and meta-analysis.

Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake.

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drug-drug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENT: The organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

Prevalence of protective haplotypes of the SLCO1B1 gene for statin transport in Mexican populations.

Aim: To evaluate the genetic distribution of the rs4149056 and rs2306283 variants in the SLCO1B1 gene in Mexican Mestizo (admixed) and Native American groups. Materials & methods: We recruited 360 volunteers who were qPCR-genotyped with TaqMan probes. Results: Allele and genotype frequencies are reported. Among the expected rs4149056-rs2306283 haplotypes, T-A (42.35-58.47%) was the most prevalent which relates to the normal activity of the OATP1B1 transporter. This was followed by the T-G haplotype associated with further statin transport and cholesterol reduction (32.49-43.76%). Conclusion: Based on these SLCO1B1 gene variants, we confirmed that a minimum fraction of the Mexican study populations would be at risk from decreasing simvastatin transport and the development of statin-induced myopathy.

Lay abstract The clinical response to statins, mainly atorvastatin and simvastatin, can be modified by interindividual variability including variations in the SLCO1B1 gene. This gene, that encodes the statin transporter OATP1B1, helps to regulate the cholesterol levels in the blood and is responsible for the presence of adverse drug reactions related to the statin consumption, such as muscular sickness. This study analyzes the distribution of the SLCO1B1 gene variants rs4149056 and rs2306283 in geographically dispersed samples of the two main populations in Mexico: two Mestizo (admixed) populations and three Native American groups. We found that the genetic combinations of T­A and T­G for the two SLCO1B1 gene variants ­ associated with normal or efficient activity of the transporter OATP1B ­ were predominant in all of the study population. Therefore, the SLCO1B1 gene variability suggests that a majority of the Mexican population will respond favorably to simvastatin and have a low risk of developing associated muscular complications.

A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis.

The aim of this study was to develop a population pharmacokinetic model of rifampicin (RMP) in Mexican patients with tuberculosis (TB) to evaluate the influence of anthropometric and clinical covariates, as well as genotypic variants associated with MDR1 and OATP1B1 transporters. A prospective study approved by Research Ethics Committee was performed at Hospital Central in San Luis Potosí, Mexico. TB patients under DOTS scheme and who signed informed consent were consecutively included. Anthropometric and clinical information was retrieved from medical records. Single nucleotide polymorphisms in MDR1 (C3435T) and SLCO1B1 (A388G and T521C) genes were evaluated. RMP plasma concentrations and time data were assessed with NONMEM software. A total of 71 Mexican TB patients from 18 to 72 years old were included for RMP quantification from 0.3 to 12 h after dose; 329 and 97 plasma concentrations were available for model development and validation, respectively. Sequential process includes a typical lag time of 0.25 h prior to absorption start with a Ka of 1.24 h-1 and a zero-order absorption of 0.62 h to characterize the gradual increase in RMP plasma concentrations. Final model includes total body weight in volume of distribution (0.7 L/kg, CV = 26.8%) and a total clearance of 5.96 L/h (CV = 38.5%). Bioavailability was modified according to time under treatment and generic formulation administration. In conclusion, a population pharmacokinetic model was developed to describe the variability in RMP plasma concentrations in Mexican TB patients. Genetic variants evaluated did not showed significant influence on pharmacokinetic parameters. Final model will allow therapeutic drug monitoring at early stages.

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial.

Atorvastatin (ATV) is a blood cholesterol-lowering drug used to prevent cardiovascular events, the leading cause of death worldwide. As pharmacokinetics, metabolism and response vary among individuals, we wanted to determine the most reliable metabolic ATV phenotypes and identify novel and preponderant genetic markers that affect ATV plasma levels. A controlled, randomized, crossover, single-blind, three-treatment, three-period, and six-sequence clinical study of ATV (single 80-mg oral dose) was conducted among 60 healthy Mexican men. ATV plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed by real-time PCR with TaqMan probes. Four ATV metabolizer phenotypes were found: slow, intermediate, normal and fast. Six gene polymorphisms, SLCO1B1-rs4149056, ABCB1-rs1045642, CYP2D6-rs1135840, CYP2B6-rs3745274, NAT2-rs1208, and COMT- rs4680, had a significant effect on ATV pharmacokinetics (P < 0.05). The polymorphisms in SLCO1B1 and ABCB1 seemed to have a greater effect and were especially important for the shift from an intermediate to a normal metabolizer. This is the first study that demonstrates how the interaction of genetic variants affect metabolic phenotyping and improves understanding of how SLCO1B1 and ABCB1 variants that affect statin metabolism may partially explain the variability in drug response. Notwithstanding, the influence of other genetic and non-genetic factors is not ruled out.

Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin.

The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0-4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP-1 and TNF-α, while the uncontrolled SLE group also showed higher plasma concentrations of IL-10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76-83.56) vs. 30.56 (22.69-41.15) ng⋅hour/mL) and its inactive metabolite ATV-lactone (98.74 (74.31-131.20) vs. 49.21 (34.89-69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30-457.00) vs. 654.5 (486.00-881.4) L/hour) and apparent volume of distribution (2,609 (1,607-4,234) vs. 7,159 (4,904-10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV-lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe.

AIMS: Rheumatoid arthritis (RA) is a long term autoimmune inflammatory disease characterized by high autoantibody production and cytokine release, especially IL-6 and TNF-α. Some clinical studies have shown the effect of RA on CYP metabolism. However, the effect of RA on the drug transporter OATP1B1 remains a gap. METHODS: Patients with RA under pharmacological treatment (n = 10) and healthy volunteers (n = 15) treated for seven consecutive days with racemic fluvastatin (20, 40, or 80 mg/24 h) were investigated. Serial blood samples were collected during the last dose interval. All participants were assessed for cytokine profile and CYP2C9 genotype. RESULTS: Patients with RA showed increased plasma concentrations of IFN-γ and TNF-α up to two and four times, respectively, when compared to healthy volunteers, whereas CYP2C9 activity based on genotype was considered normal or slightly reduced for both investigated groups. When compared to healthy volunteers, patients with RA presented higher values (median and 25th-75th percentiles) of normalized AUC for 20 mg dose (250 [114-405] vs. 96.7 [78.1-131] ng h mL-1 for (-)-3S,5R-fluvastatin and 163 [96.9-325] vs. 83.1 [61.7-107] ng⋅h⋅mL-1 for (+)-3R,5S-fluvastatin) and lower values of CL/F (40.9 [24.5-89.1] vs. 103 [75.9-128] L⋅h-1 for (-)-3S,5R-fluvastatin and 61.4 [30.6-103] vs. 120 [93.0-162] L⋅h-1 for (+)-3R,5S-fluvastatin) and V/F (73.0 [28.5-117] vs. 143 [108-221] L for (-)-3S,5R-fluvastatin and 93.9 [32.7-116] vs. 153 [122-234] L for (+)-3R,5S-fluvastatin) for both enantiomers. CONCLUSION: The lower values of CL/F and V/F for both fluvastatin enantiomers in RA patients suggest that the inflammatory disease downregulates the sinusoidal drug transporter OATP1B1, the rate-determining step in the hepatic clearance of fluvastatin.

Utilidad del gen SLCO1B1 como marcador de interés en la farmacogenómica de las estatinas / SLCO1B1 gene utility as a marker of interest in the pharmacogenomics of statins

Resumen Las enfermedades cardiovasculares son la principal causa de muerte en el mundo. Fármacos hipolipemiantes como las estatinas son la primera alternativa en la prevención primaria de eventos cardiovasculares, ictus cerebrales y procedimientos de revascularización. Estos fármacos son inhibidores de la enzima HMG-CoA reductasa, la cual regula la velocidad de la síntesis del colesterol y además aumenta la captación hepática del mismo por la vía del receptor de las LDL. El polipéptido transportador de aniones orgánicos 1B1 (OATP1B1) codificado por el gen SLCO1B1 es uno de los transportadores de captación y eflujo hepático de las estatinas. Por medio de estudios de asociación de genomas completos se han reportado diferentes SNPs dentro del gen SLCO1B1 con capacidad de reducir la captación de estatinas mediada por OATP1B1, por lo que las variaciones en la secuencia de este gen influyen en la farmacocinética y farmacodinámica de estos medicamentos, llegando a causar una condición conocida como miopatía inducida por estatinas. En la actualidad, genes que afectan las terapias cardiovasculares, así como los avances actuales en el campo de las pruebas diagnósticas basadas en la secuenciación de los mismos, ofrecen la posibilidad de revolucionar el diagnóstico y el tratamiento con el fin de validar el riesgo de predicción, pronóstico, prevención y manejo de pacientes con riesgo de enfermedades cardiovasculares, lo cual conducirá al desarrollo de nuevas formas de tratamientos médicos.

Abstract 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.

Pharmacogenomics and variations in the risk of toxicity during the consolidation/maintenance phases of the treatment of pediatric B-cell leukemia patients from an admixed population in the Brazilian Amazon.

The treatment of Acute Lymphoblastic Leukemia (ALL) in children has a high clinical success rate, although toxicological complications are frequent, and often result in the interruption of the treatment. Various studies have shown that toxicities resulting from the treatment are influenced by pharmacogenetic variants. Most of this research has focused on relatively homogeneous populations, and the influence of these variants in highly admixed populations, such as that of Brazil, is still poorly understood. The present study investigated the association between pharmacogenetic variants and severe toxicities in pediatric B-cell ALL patients from an admixed population of the Brazilian Amazon. The rs2306283 (of SLCO1B1) mutant allele increased the risk of neurotoxicity threefold, and the homozygous mutant rs9895420 (of ABCC3) genotype was associated with a fivefold increase in protection against severe gastrointestinal toxicity. This indicates that the rs2306283 and rs9895420 polymorphisms may be relevant to the prediction of severe toxicity in pediatric ALL patients.

An update on efflux and uptake transporters as determinants of statin response.

INTRODUCTION: Statins are used in the treatment of dyslipidemia promoting primary and secondary prevention against detrimental cardiovascular events. ATP-binding cassette (ABC) and solute carrier (SLC) membrane transporters transport statins across the cell membrane. Differences in drug transporter tissue expression and activity contribute to variability in statin pharmacokinetics (PK) and response. Areas covered: The purpose of this review is to discuss factors impacting transporter expression and the effect this has on statin efficacy and safety. Previous studies have demonstrated that genetic polymorphisms, drug-drug interactions (DDI), nuclear receptors, and microRNAs affect statin PK and pharmacodynamics. Expert opinion: Genetic variants of ABCG2 and SLCO1B1 transporters affect statin PK and, as a result, the intended lipid-lowering response. However, the effect size is small, limiting its applicability in clinical practice. Furthermore, genetic variants do not totally explain the observed intervariability in statin response. Thus, it is likely that transcriptional and post-transcriptional regulation of drug transporters are also highly involved. Further studies are required to understand the contribution of each of these new factors in statin disposition and toxicity.

SLCO1A2, SLCO1B1 and SLCO2B1 polymorphisms influences chloroquine and primaquine treatment in Plasmodium vivax malaria.

AIM: The association of transporters gene polymorphisms with chloroquine/primaquine malaria treatment response was investigated in a Brazilian population. PATIENTS & METHODS: Totally, 164 Plasmodium vivax malaria infected patients were included. Generalized estimating equations were performed to determine gene influences on parasitemia and/or gametocytemia clearance over treatment time. RESULTS: Significant interaction between SLCO2B1 genotypes and treatment over time for parasitemia clearance rate on day 2 were observed (p FDR = 0.002). SLCO1A2 and SLCO1B1 gene treatment over time interactions were associated with gametocytemia clearance rate (p FDR = 0.018 and p FDR = 0.024). ABCB1, ABCC4 and SLCO1B3 were not associated with treatment response. CONCLUSION: The present work presents the first pharmacogenetic report of an association between chloroquine/primaquine responses with OATP transporters.

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

SLCO1B1 c.388A>G Polymorphism Is Associated with HDL-C Levels in Response to Atorvastatin in Chilean Individuals.

The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects.

The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis.

OBJECTIVE: To determine whether three variants (388 G>A, 521 T>C, and 463 C>A) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) are associated with neonatal hyperbilirubinemia. DATA SOURCE: The China National Knowledge Infrastructure and MEDLINE databases were searched. The systematic review with meta-analysis included genetic studies which assessed the association between neonatal hyperbilirubinemia and 388 G>A, 521 T>C, and 463 C>A variants of SLCO1B1 between January of 1980 and December of 2012. Data selection and extraction were performed independently by two reviewers. SUMMARY OF THE FINDINGS: Ten articles were included in the study. The results revealed that SLCO1B1 388 G>A is associated with an increased risk of neonatal hyperbilirubinemia (OR, 1.39; 95% CI, 1.07-1.82) in Chinese neonates, but not in white, Thai, Latin American, or Malaysian neonates. The SLCO1B1 521 T>C mutation showed a low risk of neonatal hyperbilirubinemia in Chinese neonates, while no significant associations were found in Brazilian, white, Asian, Thai, and Malaysian neonates. There were no significant differences in SLCO1B1 463 C>A between the hyperbilirubinemia and the control group. CONCLUSION: This study demonstrated that the 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations; the SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations.

UGT1A1, SLCO1B1, and SLCO1B3 polymorphisms vs. neonatal hyperbilirubinemia: is there an association?

BACKGROUND: Jaundice is a physiological phenomenon; however, severe hyperbilirubinemia occurs in only 5 to 6% of the healthy newborn population. It has been suggested that genetic variation could enhance the risk of hyperbilirubinemia when coexpressed with other icterogenic conditions. METHODS: The study included newborns with a gestational age of greater than 35 wk and weights greater than 2,000 g with indications for phototherapy. The polymorphisms from UGT1A1 (rs8175347), SLCO1B1 (rs4149056 and rs2306283), and SLCO1B3 (rs17680137 and rs2117032) were analyzed by capillary electrophoresis and hydrolysis probes. RESULTS: A total of 167 hyperbilirubinemic infants and 247 control subjects were enrolled. The gender, ABO incompatibility, birth weight, and gestational age differed between the groups, but the allelic and genotypic frequency of the polymorphisms from SLCO1B genes did not. In logistic regression, the ABO incompatibility, gestational age, and polymorphic T allele of rs2117032 remained in the model. The presence of this polymorphism seemed to provide protection from hyperbilirubinemia. The individuals who were homozygous for the G allele of rs2306283 and who were glucose 6-phosphate-dehydrogenase deficient were more frequent among the cases. CONCLUSION: Although genetic variation accounts for a good part of this condition, the association between different polymorphisms and environmental factors has yet to be explained.