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Objective To study the effect of SLCO1B1 521 T>C and APOE gene polymorphisms on the clinical efficacy and safety of atorvastatin in ischemic stroke patients with dyslipidemia. Methods 210 cases of ischemic stroke with dyslipidemia were enrolled from April 2018 to December 2018 to determine SLCO1B1 521 T>C and APOE gene polymorphisms. Patients received atorvastatin 20 mg/d orally. TC, TG, HDL-C, LDL-C levels were measured to evaluate the efficacy 3 months pre-and post- treatment. TBil, ALT, AST, CK levels were assayed with following up adverse reactions to evaluate safety. Results SLCO1B1 521 T>C genotype distribution was TT79.05%, TC19.05%, CC1.90%. E2, E3, E4 allele frequencies of APOE genes were 14.28%, 67.62%, 18.10%. Each genotype conforms to the law of Hardy-Weinberg balance. After three months of medication, there were significant differences in TC, TG, LDL-C, HDL-C changes in patients with different APOE genotypes. No obvious abnormality was found in safety index. The incidence of myalgia in SLCO1B1521 T>C mutant group was significantly higher than that in the wild group (P<0.01). Conclusion Lipid regulation of atorvastatin was affected by APOE gene polymorphism. SLCO1B1521 T>C may be associated with myalgia, the adverse reaction of atorvastatin. The detection of SLCO1B1 and APOE genotyping is helpful for individualized treatment of blood lipids and provides basis for rational use of statins in patients for drug therapy management.
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AIM: To investigate the polymorphism distribution of lipid and drug metabolism-related genes of SLCO1B1 and ApoE in patients with cardiovascular disease of Han nationality in Anhui province, and to evaluate the benefit-risk ratio of individual use of statins. METHODS: PCR fluorescence probe technique was used to detect the genetic polymorphism of rs2306283 (388A>G) and rs4149056 (521T>C) of SLCO1B1 as well as rs429358 (388 T>C) and rs7412 (526C>T) of ApoE in 736 individuals diagnosed with cardiovascular diseases in the inpatient department of the Second People's Hospital of Hefei from January 2019 to August 2020 were included. The distribution characteristics of SLCO1B1 and ApoE genotypes were analyzed according to the gender of the subjects, and the results of genetic polymorphism were compared with the data of cardiovascular disease patients in other areas of China. RESULTS: Six genotypes of SLCO1B1 had been detected. They were *1a/*1a (6.11%), *1a/*1b (29.08%), *1b/*1b (44.57%), *1a/*15 (4.08%), *1b/*15 (15.49%) and *15/*15 (0.68%), while *1a/*5, *5/*5 and *5/*15 had not been detected. Six genotypes of ApoE had been detected. They were E2/E2 (0.41%), E2/E3 (11.96%), E2/E4 (1.09%), E3/E3 (67.66%), E3/E4 (17.93%) and E4/E4 (0.95%). The frequency distribution of genetic polymorphism of these two genes satisfied the Hardy-Weinberg genetic equilibrium, which was representative of the population. In this study, the proportion of people with SLCO1B1 normal myopathy risk was the highest, accounting for 79.76%; SLCO1B1 had a lower proportion of people with moderate myopathy risk and high myopathy risk were 19.57% and 0.68%, respectively. The reduced risk, normal risk and increased risk phenotypes of ApoE were respectively 12.37%, 68.75% and 18.88%. There was no statistically significant difference in SLCO1B1 and ApoE genotypes beween gender. Compared with patients with cardiovascular disease in Southern China area, the distribution of ApoE genetic polymorphism was significantly different in Anhui. CONCLUSION: The SLCO1B1 and ApoE genetic polymorphism of 736 patients with cardiovascular diseases in Anhui were mainly normal myopathy risk types with higher dose tolerance of statins as well as popular genotypes that were sensitive to statins, and the application of statins has a lower risk of myopathy and a good effect on lipid reduction. The polymorphism of the two genes was not affected by gender, but the distribution phenotypes of ApoE might be different in regional characteristics. The detection of SLCO1B1 and ApoE genetic polymorphism is significant for evaluation of benefit-risk ratios, thereby guiding statins clinical treatment.
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AIM: To explore the relationship between SLCO1B1 rs2291075 polymorphism and tacrolimus (FK506) dose-corrected trough concentration (C/D, ng•mL
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OBJECTIVE： To study the relationships of polymorphism of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus with drug concentration of methotrexate （MTX） and high-dose MTX （HD-MTX）-induced ADR in acute lymphoblastic leukemia （ALL） children. METHODS： From Oct. 2015 to Sept. 2018， 70 ALL hospitalized children of Han nationality in Sichuan area who received HD-MTX treatment and were in consolidation chemotherapy were selected retrospectively from Sichuan People’s Hospital. The blood concentration of MTX at 48 and 72 hours after administration was measured by EMIT. The genetic typing of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus were detected with real-time PCR. The relationships of the polymorphism of MTRR gene and SLCO1B1 gene with MTX blood concentration [dose-corrected concentration （c48 h/D，48 h）， the proportion of children with different concentration of MTX （≤0.1， ＞0.1 μmol/L）] and ADR （such as myelosuppression， liver function damage， gastrointestinal response， mucosal damage， rash， etc.） were analyzed. Binary Logistic regression analysis for the correlation of ADR with different influencing factors （gene polymor- phism， blood concentration of MTX， immunophenotyping， body mass index， etc.） was carried out by Wald method. RESULTS： Totally 31， 32， 7 children with MTRR gene AA， AG and GG genotype， while 23， 37， 10 children with SLCO1B1 gene TT， TC and CC genotype were detected. The distribution of each genotype in 70 children conformed to Hardy-Weinberg equilibrium （P＞0.05）. There was no significant difference in c48 h/D（48 h） of children and the proportion of children with different concentration of MTX （72 h） among difterent genotypes of MTRR and SLCO1B1 gene （P＞0.05）. There was statistical significance in the incidence of liver function injury in children with different genotypes of MTRR gene （P＜0.05）， and the AA genotype was significantly higher than the AG+GG genotype （P＜0.05）. There was no correlation of MTRR gene polymorphism with the incidence of other ADR， neither SLCO1B1 gene polymorphism with the incidence of ADR （P＞0.05）. The results of Binary Logistic regression analysis showed that liver function damage in ALL children was related to the gene polymorphism of MTRR； gastrointestinal reaction was related to whether the plasma concentration was more than 0.1 μmol/L at 72 h； mucosal damage was related to the immune type and BMI of children； the occurrence of skin allergy was correlated with body weight of children（P＜0.05）. CONCLUSIONS： Gene polymorphism of MTRR rs1801394 locus may associated with the occurrence of HD-HTX-induced liver function injury in ALL children， but its polymorphism and gene polymorphism of SLCO1B1 rs11045879 locus are not related to MTX blood concentration in ALL children.
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OBJECTIVE The purpose of the present study was to investigate the impact of fluvas-tatin formulation on the pharmacokinetics-genetic polymorphis relationship. METHODS We compared the difference between the pharmacokinetics of fluvastatin as an extended-release (ER) 80 mg tablet and an immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter ge-netic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study, ef-fects of BCRP, SLCO1B1, MDR1, CYP2C9, and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed in 24 healthy individuals.Each treatment duration was 7 days with a washout period of 7 days between the crossover.Serum concentration of fluvastatin was evaluated using high-performance liquid chromatography-tandem mass spectrometry. RESULTS The SLCO1B1 T521C genotype had no statistically significant effect on IR 40 mg capsule of fluvastatinafter single or repeated doses.However,for the ER 80 mg tablet,the SLCO1B1 T521C genotype correlated with the AUC0-24of repeat doses (P=0.01). The CYP2C9*3 genotype correlated with the AUC0- 24after the first dose IR 40 mg capsule (P<0.05); however, the difference between CYP2C9*1/*1 and CYP2C9*1/*3 was not statistically significant after repeated doses. CONCLUSION The effect of SLCO1B1 T521C on fluvas-tatin exposure was observed and was more profound in ER and repeated dose administration than in IR and single dose administration.We recommend that formulation should be incorporated into future pharmacogenomics studies and clinical implication guidelines.
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BACKGROUND: This study was performed to clarify the effect of SLCO1B1 T521C on statin-induced myotoxicity. METHODS: The PubMed, Embase, Ovid, and Cochrane Library databases were searched for all published studies between database inception and April 2018. Using Review Manager 5, the pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were determined to assess the effect of SLCO1B1 T521C on statin-induced myotoxicity by using different genetic models. RESULTS: Eleven observational studies and one randomized controlled trial were included in the meta-analysis. The pooled analysis showed that the incidence of statin-induced myotoxicity was significantly associated with the SLCO1B1 521C variant allele. Among patients using statins, the incidence of myotoxicity was higher in those carrying the 521TC or 521CC variant than in those carrying the 521TT variant in the dominant model (TC + CC vs TT, OR: 1.57; 95% CI: 1.20, 2.05; p = 0.001). The 521TC genotype was associated with a higher risk of myotoxicity than the 521TT genotype (OR: 1.42; 95% CI: 1.09, 1.86; p = 0.009). Furthermore, the incidence of myotoxicity was higher in 521CC carriers than in 521TC carriers (OR: 1.40; 95% CI: 1.06, 1.83; p = 0.02) and noticeably higher in 521CC carriers than in 521TT carriers (OR: 2.26; 95% CI: 1.23, 4.17; p = 0.009). CONCLUSION: The identification of individuals with the SLCO1B1 521C variant allele prior to the initiation of statin therapy might be useful to predict the risk of toxicity development, determine the individual dose, and prevent myotoxicity.
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Humanos , Alelos , Genotipo , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Incidencia , Modelos Genéticos , Oportunidad RelativaRESUMEN
Objective To verify the performance characteristics of the human SLCO1B1 & APOE gene detection kit (PCR-fluorescent probe technique).Methods The verification protocol for the human SLCO1B1 & APOE gene detection kit manufactured by Wuhan YZY Medical Science and Technology Co.,Ltd.was designed by referring to the requirements of professional standard and pertinent literatures,and its accuracy,specificity,lowest detection limit and anti-interference ability were compared with those of sequencing technique (gold standard).Results The results coincidence of 20 clinical samples from fluorescence PCR and sequencing technique was 100％,which met the requirement of accuracy.Forty clinical samples with wild type loci determined by fluorescence PCR were verified by sequencing and no any mutation was detected,which met the requirement of specificity.The lowest detection limit of the kit was 10 ng/μL.Three interfering substances,including hemoglobin,bilirubin and triglyceride,were individually added into the blood samples with known genotype,and the results determined by the kit were coincident with that without interfering substances,which met the requirement of anti-interference ability.Conclusion The verification parameters of the human SLCO1B1 & APOE gene detection kit are basically consistent with the manufacturer's statement,indicating that the kit meets the requirements of the relevant quality management and may be applied to the detection of clinical samples.
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Objective To investigate the frequency distribution of ApoE and SLCO1B1 genotypes in abnormal blood lipid lev-els in Xiangya Hospital,explore the correlation of ApoE and SLCO1B1 genotypes with various indicators of dyslipidemia,and provide evidence for prevention and treatment of atherosclerotic diseases.Methods Blood lipid data including TG,TC,LDL-C and HDL-C in 87 cases of dyslipidemia people in Xiangya Hospital from June in 2016 to April in 2017 were collected.The ApoE and SLCO1B1 genotypes were detected by PCR fluoroscopy in 87 cases of dyslipidemia.The distribution of gene fre-quency was analyzed and the differences of blood lipid indexes among the genotypes were compared.Results The frequen-cies of each ApoE genotype in 87 cases of dyslipidemia were E2/E2 1.15%,E2/E3 13.79%,E2/E4 1.15%,E3/E3 56.32%,E3/E4 26.44% and E4/E4 1.15%,respectively.The highest proportion of allele frequency was E3 with the per-cent of 76.44%,E2 and E4 occupied 8.62% and 14.94%,respectively.The concentration of LDL-C in E4 phenotype group was higher than that in E2 group and E3 group,and there was no significant difference in the levels of TG,TC,LDL-C and HDL-C.The frequencies of each SLCO1B1 genotype were *1a/*1a 6.90%,*1a/*1b 36.70%,*1a/*15 13.79%,*1b/*1b 26.44% and *1b/*15 16.09%.The highest frequency of each haplotype was *1b with the percent of 52.87%,*1a and *15 occupied 32.18% and 14.94%,respectively,and no * 5 type was detected.There were no significant differ-ences in TG,TC,LDL-C and HDL-C concentrations between SLCO1B1 groups.Conclusion ApoE gene frequency distribu-tion was uneven.Its polymorphism be related with the lipid levels.The frequency distribution of SLCO1B1 gene had racial differences,and its polymorphism was not related with lipid level.According to the the genotypes of ApoE and SLCO1B1, clinician can choose the right dose of drug to prevent coronary atherosclerotic disease.
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Objective To establish the allele-specific real-time polymerase chain reaction (ASPCR) for detection of neonatal hyperbilirubinemia related gene SLCO1B1 A388G polymorphism and apply this assay to identify the clinical samples.Methods According to SLCO1B1 A388G polymorphism loci,specific primers were designed and the assay was established.Wide type plasmid and mutant plasmid were constructed.Fifty clinical samples were selected,including 30 samples of neonatal hyperbilirubinemia that had been diagnosed with SLCO1B1 A388G mutant and 20 samples of healthy newborns without SLCO1B1 A388G mutant were selected as the controls.Wide type plasmid,mutant plasmid and clinical samples were tested by specific and non-specific primers.A388G polymorphism was determined by difference in Ct (cycle threshold) between specific and non-specific primers.Then,the accuracy,sensitivity and specificity of assay were evaluated.Results The difference in Ct (cycle threshold) between specific and non-specific primers that amplified equivalent wide type template was 13.97 ±0.75.The assay could correctly distinguish the wide type and mutant plasmid.Probit regression analysis showed the sensitivity of the assay could reach to 5.28 copies/μL.For clinical samples,the Ct values of the samples with A388G mutation was less than 37.75 and showed positive results,while the samples without A388G mutation did not show any amplification nor Ct values were larger than 37.75,which showed negative results.Conclusions ASPCR is a fast,simple and effective method for SLCO1B1 A388G polymorphism detection of the clinical simples.It can be used for large sample screening for neonatal hyperbilirubinemia gene loci.
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Objective To investigate the association between SLCO1B1/ApoE gene polymorphisms and lipid-lowering efficacy and safety of rosuvastatin.Methods DNA samples were extracted from blood using nano paramagnetic particle method.The SLCO1B1 521T＞C and ApoE gene polymorphisms were screened by PCR-pyrophosphate sequencing method.Totally 152 patients received rosuvastatin orally at a dose of 10 mg/d.The lipidlowering efficacy was evaluated through detecting serum low-density lipoprotein cholesterol (LDL-C) level before and 8 weeks after the treatment.The incidence of myopathic adverse effect was assessed by follow-up of the occurrence of myalgia.Results The gene distribution of SLCO1B1 521T＞C was 73.7％,23.7％ and 2.6％ respectively for TT,TC and CC in 152 patients,and the distribution of ApoE gene was 65.8％,13.2％ and 21.0％ respectively for ε3/ε3,ε3/ε2 and ε4/ε3.The genotype ε4/ε4,ε2/ε2 and ε4/ε2 were not detected.After orally receiving rosuvastatin 10 mg daily for 8 weeks,the decreased LDL-C levels showed significant differences (P＜0.05) among ApoE genotype ε3/ε2,ε3/ε3 and ε4/ε3 groups,and the frequencies of myalgia showed significant differences in the three genotype groups of SLCO1B1 521T＞C (P＜0.05).Conclusion The gene polymorphism of SLCO1B1/ApoE was correlated with efficacy and safety of rosuvastatin.The combined detection of SLCO1B1/ApoE genes can be utilized to predict efficacy and risk,and then realize individualized medication.
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The study aims to investigate the associations of SLCO1B1 polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients. Blood samples and clinical data were collected from 89 renal transplant recipients with tacrolimus treatment. CYP3A5*3 genotypes were detected by PCR-RFLP method and SLCO1B1 (rs2306283, rs4149032) genotypes were detected by Agena Bioscience Mass ARRAY ® system. Trough concentrations of tacrolimus on day 7 after renal transplantation were collected from clinical data. Correlations between genetic polymorphisms and tacrolimus concentrations were analyzed by SPSS. In CYP3A5 nonexpressers, the dose-adjusted concentration of tacrolimus in SLCO1B1 rs2306283 CC carriers was considerably higher than that in CT and TT carriers. The results illustrated that SLCO1B1 rs2306283 polymorphisms were associated with tacrolimus concentrations, and genotyping for this SNP may be usefulfo r individualized medicine of tacrolimus.
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BACKGROUND: Several studies have focused on the association between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism; however, the results are conflicting. The effects of statins show significant variability between individuals. This meta-analysis aimed to investigate the effects of the SLCO1B1 c.521T>C polymorphism on the lipid-lowering effects of statins. METHODS: We systematically searched PubMed and Web of Science to screen relevant studies. Meta-analysis was performed to identify the association between SLCO1B1 c.521 polymorphisms and the lipid-lowering effects of statinson the basis of the standard mean difference (SMD) and 95% confidence intervals (CIs). Additionally, we checked for heterogeneity (I 2) among studies and evidence of publication bias. We obtained eight studies including 2,012 wild genotype (T/T) and 526 variant genotype (T/C and C/C) cases. RESULTS: No significant difference was observed in the lipid-lowering efficacy of statins between the wildand variant genotypes of SLCO1B1, with a pooled SMD of 0.03 (95% CI: -0.07-0.13). Furthermore, there was no significant effect in the meta-analyses of the variant heterozygote, homozygote, and Chinese populations. Subgroup meta-analysis indicated that the timerequired for the statin to take effectdid notsignificantly affect the association between lipid-lowering efficacy of statins and SLCO1B1 c.521T>C polymorphism. However, thewild genotype improved the lipid-lowering efficacy of simvastatin with a pooled SMD of -0.26 (95% CI: -0.47- -0.05). CONCLUSIONS: No significant association was detected between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism, with the exception of simvastatin.