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AIM: To elucidate the relationship between childhood asthma susceptibility and clinical efficacy of inhaled glucocorticoids (ICS) in children with different genotypes of asthma by exploring rs776746 and rs15524 single nucleotide polymorphisms (SNPs) of cytochrome P450 enzyme 3A5 (CYP3A5) gene in asthmatic children and healthy children. METHODS: The CYP3A5 gene rs776746 and rs15524 polymorphic sites were detected in 79 children (Case group) with asthma of Han nationality and 100 healthy children (Control group) who met the inclusion criteria admitted to the Northern Theater General Hospital in Northeast China from October 2016 to October 2020, and genotype, allele and linkage analysis were performed. The case group was given inhaled glucocorticoids by nebulised inhalation for 3 months, and lung function and exhaled breath nitric oxide (FeNO) were measured at entry and after treatment, and asthma control score C-ACT/ACT was done after treatment, so as to compare the prevalence of different genotypes and the differences in the above test index scores. RESULTS: There was complete linkage disequilibrium at rs776746 and rs15524 loci. There were three genotypes of T/T, T/C and C/C at rs776746 locus of CYP3A5 gene. There were significant differences in the frequency of different genotypes between the case group and the control group (χ
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Wuzhi tablet (WZ) is a prescribed herbal medicine extracted from Schisandra sphenanthera, which is widely used to protect the liver injury and drug-induced hepatotoxicity in clinical practices. Previous studies showed that WZ significantly increased the blood concentrations of tacrolimus, cyclosporine A, paclitaxel by inhibiting the cytochrome P450 3A (CYP3A)-mediated metabolism. CYP3A4 and CYP3A5 are the most important isoenzymes among the CYP3A subfamily. However, there are some differences in the catalytic and inhibitory activities between CYP3A4 and CYP3A5, which may lead to different risk of drug-drug and herb-drug interactions, and the risks may be further amplified in vivo. Currently, few reports have compared the herbal medicine inhibitory effects between CYP3A4 and CYP3A5 mediated metabolic reactions. Therefore, detailing the inhibitory effect of WZ on CYP3A4 and CYP3A5 will help understand and predict the potential herb-drug interaction. The results showed that WZ inhibited CYP3A4 and CYP3A5 in a NADPH-, time- and concentration- dependent manner. WZ showed more potent inhibition on CYP3A5 than CYP3A4. Cautions warranted when combining WZ with other therapeutic drugs to avoid the potential herb-drug interaction.
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AIM: To investigate the influence of CYP3A5 gene polymorphism on the anti-hypertensive efficacy of calcium channel blocker in patients with ischemic stroke and hypertension. METHODS: A total of 108 cases of ischemic stroke patients with hypertension were included and divided into experimental group and control group, and 54 cases in each group, the experimental group selected amlodipine tablets and levamlodipine tablets respectively according to the results of genetic testing, while the control group selected amlodipine tablets, which in order to investigate the antihypertensive efficacy of the two groups. RESULTS: The effective rate of experimental group and control group was 77.78% and 57.41% (P 0.05). In the experimental group, the antihypertensive effect of GG and AG genotype patients after taking amlodipine tablets was significantly higher than that of AA type patients, and GG type patients had a stronger antihypertensive effect than AG type patients after taking amlodipine tablets. CONCLUSION: CYP3A5 gene polymorphism is very important for blood pressure control by calcium channel blockers in patients with ischemic stroke and hypertension.
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Objective To investigate the effect of CYP3A5 and MDR1 gene polymorphisms on blood concentration of tacrolimus and creatinine level in uremic patients during the early phase after kidney transplantation in real clinical practice. Methods 131 patients who underwent kidney transplantation for the first time with triple immunotherapy based on tacrolimus in single-center from 2013 to 2017 were enrolled for retrospective study. Tacrolimus daily dose, blood concentration, blood concentration-to-dose ratio, and serum level were compared according to the various genotypes of CYP3A5 and MDR1 polymorphisms in renal transplantation recipients, respectively. Results The dosage of tacrolimus in CYP3A5*3/*3 (GG) kidney transplantation recipients within 4 weeks after kidney transplantation was lower than those of CYP3A5*1/*1 (AA) and CYP3A5*1/*3 (AG). The serum creatinine levels of patients whose tacrolimus concentration in the range of 10-13 ng/ml were close to the normal value. Conclusion CYP3A5 gene polymorphism affects the blood concentrations of tacrolimus in renal transplant recipients. No association has been found between the blood concentrations of tacrolimus and MDR1 gene polymorphism. Tacrolimus concentration in the range of 10-13 ng/ml might contribute to restore the early kidney graft function.
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@#CYP3A4 and CYP3A5 are metabolizing enzymes abundantly expressed in liver and involved in the metabolism of xenobiotics as well as clinically used drugs. Genetic polymorphisms in CYP3A4 and CYP3A5 may alter the metabolic ability of individuals. Thus, CYP3A4 and CYP3A5 might play an important role in the aetiology of chronic myeloid leukaemia (CML) and as modulators of cancer therapy response. In this study, the impact of two single nucleotide polymorphisms (SNPs) CYP3A4*18 (878T>C) and CYP3A5*3 (6986A>G) on CML susceptibility risk was investigated. This case-control study involved a total of 520 study subjects comprising 270 CML patients and 250 normal healthy controls. Genotyping of CYP3A4*18 and CYP3A5*3 was performed by polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and CML susceptibility risk was assessed by logistic regression analysis, deriving odds ratio (OR) with 95% confident intervals. The results showed that heterozygous (*1/*1*8) genotype of CYP3A4*18 was significantly associated with CML susceptibility risk (OR 3.387; 95% CI: 1.433–8.007, p = 0.005). No homozygous variant (*18/*18) genotype was detected in this study. On the contrary, homozygous variant (*3/*3) and heterozygous (*1/*3) genotypes of CYP3A5*3 were associated with significantly lower risk for CML susceptibility (OR 0.140; 95% CI: 0.079–0.246’ p < 0.001 and OR 0.310; 95% CI: 0.180–0.535, p < 0.001, respectively). The results prompt us to conclude that genetic variation in CYP3A4*18 may contribute to a higher risk whereas CYP3A5*3 polymorphism confers a lower susceptibility risk in Malaysian CML patients.
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Objective To summarize the therapeutic effects of living related donor liver transplantation for Crigler-Najjar syndrome type Ⅰ (CNS type Ⅰ). Methods A 3-month-old male infant had appeared a progressive xanthochromia of the skin and sclera 4 d after birth without obvious cause. Other causative factors were eliminated after relevant tests were completed, and identified as CNS type Ⅰ by genetic testing. Living related donor liver transplantation was performed with his mother as the donor. An immunosuppression regimen was routinely applied postoperatively and tacrolimus doses were adjusted according to biochemical indicators and cytochrome P450 (CYP) 3A5 genotype of the recipient. Results The liver enzymes of the recipient returned to normal at 7 d postoperatively, and bilirubin decreased daily and fell to the normal range at 22 d postoperatively. Followed up to the submission date, the recipient's xanthochromia of skin and scleral faded with normal bilirubin and stable liver enzymes. The condition of the recipient was generally good with high quality of life. Conclusions Living donor liver transplantation can treat unconjugated hyperbilirubinemia and other diseases caused by CNS type Ⅰ, which greatly improve the quality of life of patients.
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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 investigate the influence of patients' genetic and clinical parameters on tacrolimus dosage and concentration after lung transplantation. METHODS: A total of 50 patients who had received lung transplantation in our hospital from April 2017 to August 2018 were enrolled in this study. Information was collected 1 year after transplantation. Tacrolimus concentration was determined by chemiluminescent microparticle immunoassay (CMIA) and CYP3A5 genotype was detected by Sanger sequencing. Body weight adjusted dosage (D) and dosage adjusted concentration (C/D) were calculated. Influence of CYP3A5 genotype on D and C/D were analyzed. Multiple linear regression was performed to determine influential factors on tacrolimus dosage 1 year after lung transplantation. RESULTS: While maintaining tacrolimus concentration within therapeutic range, dosage requirement for CYP3A5*1/*1 and *1/*3 patients was higher than that of *3/*3 patients and C/D value was lower than that of *3/*3 patients (P<0.05). Multivariable linear regression results showed that CYP3A5 genotype, hemoglobin and age had significant influence on tacrolimus D, among which hemoglobin and age showed negative correlation (P<0.05). Prediction equation for tacrolimus D was obtained by multivariable linear regression. The correlation coefficient between predicted dose and actual dose was 0.824 (95% CI: 0.705-0.893). CONCLUSION: Tacrolimus dosage after lung transplantation is influenced by CYP3A5 genotype, hemoglobin and age. Using these factors for tacrolimus dosage prediction could possibly be instructive for individualized use of tacrolimus.
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To determine the relationship between the effect of wuzhi capsules on the blood concentration of tacrolimus as compared to diltiazem and with regard to cytochrome P450 (CYP)3A5 gene polymorphisms, 170 patients who underwent renal transplantation from November 2014 to March 2018 and used tacrolimus combined with diltiazem 30 mg bid were selected in this study retrospectively. Patients were divided into an observation group (105 patients) and a control group (65 patients) according to whether they used wuzhi capsules after the operation. The polymorphisms of CYP3A5*3 were determined and the effect of wuzhi capsules on the blood concentration of tacrolimus, as compared with that of diltiazem was determined in patients with different CYP3A5*3 genotypes. This study complies with relevant ethical norms. The results show that compared with diltiazem, an increase of tacrolimus C0/D was significantly correlated with the patient's CYP3A5*3 genotype in both the self-control and the control group. CYP3A5 expressers in the observation group were able to increase the tacrolimus C0/D by about 76.8% by replacing the wuzhi capsules with diltiazem, but this effect was not observed in CYP3A5 non-expressers. In CYP3A5 expressers wuzhi capsules had a greater ability relative to diltiazem to increase the blood concentration of tacrolimus.
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BACKGROUND/AIMS: The pharmacokinetics of tacrolimus (TAC) is known to be largely influenced by single-nucleotide polymorphisms (SNPs) in CYP3A5. Patients starting TAC require careful dose adjustment, owing to the wide range of optimal dosages, depending on their CYP3A5 expression status. Here, we evaluated whether individualization of TAC dosages based on CYP3A5 SNPs would improve its therapeutic efficacy in ulcerative colitis. METHODS: Twenty-one patients were prospectively treated, with their initial dosage adjusted according to their CYP3A5 status (0.1, 0.15, and 0.2 mg/kg/day for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively). Their clinical outcomes were compared with those of patients treated with a fixed dose (0.1 mg/kg/day). RESULTS: The first blood trough level of CYP3A5 expressors, CYP3A5*1/*3 or CYP3A5*1/*1, and the overall rate in achieving the target blood trough level within a week in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, P=0.035 and 12.5% vs. 66.7%, P=0.01). The remission rate at 2 weeks in the expressors was as high as that in the nonexpressors, CYP3A5*3/*3, in the individualized-dose group. CONCLUSIONS: Individualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype.
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Humans , Colitis, Ulcerative , Cytochrome P-450 CYP3A , Genotype , Pharmacokinetics , Polymorphism, Single Nucleotide , Prospective Studies , Tacrolimus , UlcerABSTRACT
OBJECTIVE： To systematically evaluate the correlation between CYP3A5 6986A＞G gene polymorphism and blood concentration of Cyclosporine A （CsA） in Chinese renal transplant recipients. METHODS： Retrieved from Cochrane Library， PubMed， Embase， CBM， CNKI， VIP and Wanfang database， case-control or cohort studies about Chinese patients receiving CsA immunosuppressive therapy and blood concentration monitoring after kidney transplantation were collected. After literature screening and data extracting， the quality of literature was evaluated with Newcastle Ottawa scale， and Meta-analysis was performed by using Rev Man 5.3 software. RESULTS： Eight literatures with a total of 890 patients were involved in cohort study. Meta-analysis showed that the trough concentration after dosage correction （C0/D） of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*1/*3 genotype[MD＝－6.97，95％CI （－13.18，－0.76），P＝0.03]. The subgroup analysis showed that the C0/D of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*1/*3 genotype when test time≤1 month after renal transplant [MD＝－8.50，95％CI（－12.57，－4.43），P＜0.000 1] and ＞1-＜6 months after renal transplant [MD＝－14.02，95％CI（－26.28， －1.76），P＝0.02]. C0/D of CsA in CYP3A5*1/*3 genotype was significantly lower than CYP3A5*3/*3 genotype [MD＝－6.04，95％CI（－8.99，－3.09），P＜0.000 1]. The subgroup analysis showed that C0/D of CsA in CYP3A5*1/*3 genotype was significantly lower than CYP3A5*3/*3 genotype when test time ≤1 month after renal transplant [MD＝－6.94，95％CI（－10.21， －3.68），P＜0.000 1]. C0/D of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*3/*3 genotype [MD＝－12.64，95％CI（－21.09，－4.20），P＝0.003]. The subgroup analysis showed that C0/D of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*3/*3 genotype when test time ≤1 month after renal transplant [MD＝－16.69，95％CI（－24.03，－9.36），P＜0.000 01] and ＞1-＜6 months after renal transplant [MD＝－16.78，95％CI（－28.63，－4.93），P＝0.006]. There was no statistical significance in CsA of peak concentration after dose correction between CYP3A5*1/*1 genotype and CYP3A5*1/*3 genotype， CYP3A5*1/*3 genotype and CYP3A5*3/*3 genotype， CYP3A5*1/*1 genotype and CYP3A5*3/*3 genotype. CONCLUSIONS： CYP3A5 6986A＞G gene polymorphism is associated with C0/D of CsA in Chinese renal transplantation recipients. The sequence of C0/D when test time ≤1 month after renal transplantation is as follows as CYP3A5*1/*1 genotype＜CYP3A5*1/*3 genotype＜CYP3A5*3/*3 genotype； during＞1-＜6 months after renal transplantation， C0/D of CsA in CYP3A5*1/*1 genotype＜CYP3A5*1/*3 genotype and CYP3A5*1/*1 genotype＜CYP3A5*3/*3 genotype.
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Objective To provide a reference for the individualized medication of tacrolimus in children after living related liver transplantation,according to the effect of CYP3A5 genotyping on the concentration/dose ratio of tacrolimus in children with living related liver transplantation.Methods Peripheral blood samples were collected from children with living related liver transplantation in the transplant center.The CYP3A5 genotype was determined by polymerase chain reaction (PCR)pyrosequencing.Related indicators such as tacrolimus dose and concentration in children with living related liver transplantation were collected within 3 months after operation.According to the donor/receptor genotype,the donor/receptor expression group,the donor/receptor single expression group,and the donor/receptor non-expression group were set up.Tacrolimus concentration/dose (C0/D) ratio was statistically analyzed at 5th day,7th day,14th day,28th day,2nd month and 3rd month after administration.Results Among the 76 patients,there were 21 patients (27.63％) in CYP3A5 donor/receptor non-expression group,27 patients (35.53％) in donor/receptor single expression group,and 28 patients (36.84％) in the donor/receptor expression group.The time to the target concentration range (C0＞8 ng/mL) in CYP3A5 donor/receptor expression group was longer than in donor/receptor single expression group and donor/receptor non-expression group.Except for the individual time points,there were significant differences between CYP3A5 donor/receptor expression group and donor/receptor non expression group,or between donor/receptor non-expression group and donor/receptor single expression group,or between donor/receptor expression group and donor/receptor single expression group at rest time points (P＜0.05 for all).Conclusion In the CYP3A5 donor/receptor gene expression group,the higher dose was needed to reach the target concentration range than the gene single expression group and the donor/receptor non-expression group.Except for individual time points,there were significant differences in C0/D at rest different time points.Regardless of whether the donor or recipient contained the CYP3A5* 1 allele,C0/D was lower than the non-expressed type of the gene.Considering the polymorphism of the donor/receptor CYP3A5 gene,it was worthful for children with living related liver transplantation to allow the drug concentration to reach the therapeutic window as soon as possible and reduce organ rejection and adverse reactions.
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Objective: To investigate the effects of different CYP3A5 genotypes on the concentrations of tacrolimus in blood of the patients after kidney transplantation, and to provide the valuable evidence for personalized administration in the patients after kidney transplantation. Methods: The clinical materials of 115 patients after kidney transplantation were analyzed retrospectively. The patients were divided into three groups according to the CYP3A5 genotypes: CYP3A5 ∗ 1/ ∗ 1 group (11 cases), CYP3A5 ∗ 1/ ∗ 3 group (46 cases) and CYP3A5 ∗ 3/ ∗ 3 group (58 cases). The concentration/dosage (C0/D) values of tacrolimus in blood of the patients in three groups at 7 d, 1 month, 3 months, 6 months, 1 year, and 2 years after operation were detected, respectively. Results: Thedifferences of body mass index (BMI), age composition ratios and gender composition ratios of the patients were not significant between three groups (P>0. 05). Compared with CYP3A5 ∗ 1/ ∗ 3 group, the C0/D values of tacrolimus in blood of the patients in CYP3A5 ∗ 1/ ∗ 1 group at 7 d, 3 months, 1 year and 2 years after operation were decreased (P=0. Oil, P<0.01, P=0.022, P=0.024); compared with CYP3A5 ∗ 3/∗ 3 group, the C0/D values of tacrolimus in blood of the patients in CYP3A5 ∗ 1/ ∗ 1 group and CYP3A5 ∗ 1/ ∗ 3 group at 7 d, 1 months, 3 months, 6 months, 1 year and 2 years after operation were decreased (P
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Objective To investigate the effect of CYP3A5 on the proliferation of pancreatic cancer cells and its underlying mechanisms.Methods The protein expression of CYP3A5 in five pancreatic cancer cell lines BxPC-3,FG,MDA28,8902 and PANC1 was detected by Western blotting.The PANC1 cells with the lowest protein expression of CYP3A5 and the BxPC-3 cells with highest expression of CYP3A5 were transfected with CYP3A5 overexpression plasmid and CYP3A5 targeted-siRNA (siRNA-CYP3A5),respectively.CCK-8 and cloning formation assay were used to investigate the role of CYP3A5 overexpression and knockdown in the proliferation of pancreatic cancer cells.The changes of the protein and mRNA expression of cell cycle regulating gene cyclin E,cyclin D1 and apoptosis related gene Bcl-2 were detected by Western blotting and PCR,respectively.Results CYP3A5 protein expression in PANC1 cells increased significantly after the transfection of CYP3A5 overexpression plasmid (1.66 ± 0.14 to 1,P =0.0021),which greatly decreased in BxPC-3 cells transfected with siRNA CYP3A5 (0.18 ± 0.02 to 1,P ＜0.0001).A450 values of the CYP3A5 overexpression group and the empty plasmid group in PANC1 cells cultured for 48 and 72 h were 1.36 ±0.05 vs 1.15 ± 0.03,2.1 ± 0.09 vs 1.42 ± 0.03,respectively,which were significantly higher in CYP3A5 overexpression group than empty plasmid group,and the differences were statistically significant (P value ＜ 0.005 or 0.001).The A450 values of BxPC-3 cells in CYP3A5-siRNA transfected group and siRNA-NC transfected group were 0.62 ±0.01 vs 0.77 ± 0.03、0.83 ± 0.01 vs 1.18 ± 0.02,respectively,which in The CYP3A5-siRNA transfection group was significantly lower than that of siRNA-NC transfection group,and the difference was statistically significant (P ＜ 0.05 or ＜ 0.001).The clone formation rate of PANC1 cells in the overexpression group was (19.33 ± 0.58)％,which was significantly higher than that in the empty plasmid group (9.67±0.63) ％,and the clone formation rate in CYP3A5-siRNA group was (8.5± 0.8)％,which was significantly lower than that of group siRNA-NC (16± 0.6)％,and the differences were statistically significant (P ＜0.01).The protein expression of cyclin D1 in CYP3A5 overexpression PANC1 cells was 2.00 ± 0.11,which was obviously higher than 1.00 in empty plasmid group (P ＜0.01).The protein expression of cyclin D1 in siRNA CYP3A5 BxPC cells was 0.45 ±0.04,which was obviously lower than 1.00 in siRNA NC group,and the difference was statistically significant (P＜0.01).However,CYP3A5 overexpression or inhibition did not influence the relative expression of cyclin D1 mRNA and cyclin E,Bcl-2 pretein expression.Conclusions CYP3A5 can promote the proliferation of pancreatic cancer cells by up-regulating cyclin D1 protein expression.
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Objective To explore the feasibility and clinical significance of individualized formular administration of tacrolimus after renal transplantation based on the CYP3A5 and MDR1 gene polymorphism.Methods Total 129 renal transplantation recipients from Oct.1,2015 to July 30,2016 were included in this study and divided into 2 groups.In experimental group,tacrolimus was administrated by the individualized formula based on CYP3A5 and MDR1 gene polymorphism;in control group,tacrolimus was administrated by doctors' experience based on patient's body weight.The blood trough level of tacrolimus was determined 3 days after administration.The first blood trough level of tacrolimus,plasma creatinine level,acute rejection rate,and necessity for dialysis were compared between two groups.Results The first blood trough levels of tacrolimus in experimental and control groups were 9.24 ± 2.32 and 9.39 ± 3.47μg/L respectively (P＞0.05).The tacrolimus levels of 7 cases in experimental group and 18 cases in control group were not in normal range (P＜0.05).The plasma creatinine level at day 7 after surgery was 157.36 ± 110.55 μg/L in experimental group,and 174.01 ± 130.68μg/L in control group (P＞0.05).Acute rejection was found in both two groups:2 in experimental group and 5 in control group (P ＞ 0.05).There was significant difference in necessity for dialysis between two groups:4 in experimental group and 10 in control group (P＜0.05).Conclusion The individualized formular administration of tacrolimus based on the CYP3A5 and MDR1 gene polymorphism is more feasible and reasonable than experimental administration,which is more easier to come to an appropriate blood level and would benefit the early recovery of renal function.
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Objective To investigate the relationship between the metabolic rate of tacrolimus (FK506) and BK virus infection early after renal transplantation. Methods Eighty recipients undergoing allogenic renal transplantation in Institute of Organ Transplantation of the 309thHospital of Chinese People's Liberation Army were recruited in this study. The polymorphism of cytochrome P450 (CYP) 3A5 gene was detected in 80 recipients. All patients were divided into fast metabolism group ( CYP3A5*1/*3 and CYP3A5*1/*1 genotypes, n=38) and slow metabolism group ( CYP3A5*3/*3 genotype, n=42) based on the gene detection results. The distribution of CYP3A5 genotypes in 80 recipients was analyzed. The metabolic rate [concentration/dose ratio (C/D value)] of FK506 was statistically compared between two groups. The incidence of BK virus infection events [BK viruria, BK viremia and BK virus nephropathy(BKVN)] within postoperative 6 months were compared between two groups. Results Among 80 recipients, 5 cases (6%) were detected with CYP3A5*1/*1 genotype, 33 (41%) with CYP3A5*1/*3 genotype, and 42 (53%) with CYP3A5*3/*3 genotype. Among the 160 alleles in 80 recipients, 117 CYP3A5*3 allele were identified, suggesting that the mutation rate of CYP3A5*3 allele was 73.1%. In the fast metabolism group, the C/D values at postoperative 1, 3, and 6 months were significantly lower than those in the slow metabolism group (all P<0.01). The incidence rates of BK viruria in the fast and slow metabolism groups were 37% and 29%, 18% and 2% for BK viremia, and 3% and 0 for BKVN, respectively. In the fast metabolism group, the incidence of BK virenia was significantly higher than that in the slow metabolism group (P=0.02). The incidence of BK viruria and BKVN did not significantly differ between two groups (both P>0.05). Conclusions According to the CYP3A5 genotyping outcomes, the recipients with a high metabolic rate of FK506 have a high risk of BK viremia early after renal transplantation.
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OBJECTIVE:To investigate the influence of CYP3A5*3 (rs776746) genetic polymorphism on blood concentration of tacmlimus (TAC) and renal function in renal transplant recipients during the stable period.METHODS:A total of 98 renal transplant recipients during the stable period receiving TAC-based triple anti-rejection scheme (TAC + sodium mycophenol +predrnisone acetate) after surgery and regular follow-up were selected from our hospital during Jan.1995-Dec.2014.The follow-up information during Jan.-Dec.2016 was also collected.Trough concentration of TAC in renal transplant recipients was determined by chemiluminescence microparticle immuno assay.Standard blood concentration (C/D) was calculated after corrected with body weight and daily dose.Scr level was detected with dry chemistry method.CYP3A5*3 genotype was detected by PCR-RFLP and direct sequencing.The relationship of CYP3A5*3 genetic polymorphism with TAC C/D value and Scr level was determined by Kruskal Wallis H or Mann-Whitney U assay.RESULTS:Among 98 renal transplant recipients,there were 9 cases of CYP3A5*3 *1/*1(AA) genotype,37 cases of *1/*3 (AG) genotype and 52 cases of *3/*3 (GG)genotype.The gene frequencies were 9.18％,37.76％,53.06％,which were all in line with Hardy-Weinberg equilibrium (P＞0.05).There was no statistical significance in trough concentration of TAC among different genotypes (P＞0.05).There was statistical significance in TAC dose and C/D value among different genotypes (P＞0.05).TAC dose of CYP3A5*3 *3/*3 genotype recipients was significantly lower than those of *1/*3 and *1/*1 genotype recipients;that of *1/*3 genotype recipients was significantly lower than that of *1/*1 genotype recipients.C/D value of *3/*3 genotype recipients was significantly higher than those of *1/*3 and *1/*1 genotype recipients;that of *1/*3 genotype recipients was significantly higher than that of *1/*1 genotype recipients,with statistical significance (P＜0.05).There was no statistical significance in Scr levels among different genotypes (P＞0.05).CONCLUSIONS:CYP3A5*3 genetic polymorphism significantly influences blood concentration of TAC in renal transplant recipients during the stable period,and *3 allele carriers have higher C/D values and need smaller TAC daily dose.CYP3AS*3 genetic polymorphism may be not associated with Scr level.
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Objective To evaluate the effect of CYP3A5 genetic polymorphisms on tacrolimus (Tac) concentration/dosing and other clinical outcomes in a pilot cohort of 113 Chinese HTx recipients.Methods Association between CYP3A5 genetic variants and blood dose-adjusted trough concentrations (C0/D) of Tac at 1st month at the beginning of the immunosuppressive therapy was evaluated in cohorts of 113 patients,then at 1st,3rd,6th,and 12th months after transplantation in 41 patients who received Tac-based immunosuppressive therapy and never changed within one year after transplantation,respectively.In addition,we also evaluated the association between CYP3A5 genetic variants and other clinical outcomes,such as the classifications of endomyocardial biopsy and longterm prognosis.Results The CYP3A5 wild homozygote (* 1/* 1),mutant homozygote (* 3/* 3),and mutant heterozygote (* 1/* 3) occurred in 5,34 and 74 recipients respectively.The gene mutation rate of CYP3A5 in this cohort of Chinese HTx recipients was 80.5 ％ and the homozygous proportion was 65.5％.Compared with CYP3A5 expressors (* 1/* 1 or * 1/* 3),CYP3A5 nonexpressors (* 3/* 3) had a higher Tac C0/D at 1st month (47.34 ± 11.40 vs.116.11 ± 42.40 vs.293.70 ± 171.20,P =0.000),as well as other studied time points (3rd month:98.32 ± 39.43 vs.292.07 ± 141.08,P=0.003;6th month:90.00 ± 21.31 vs.341.68 ± 165.02,P =0.002;and 12th month:96.02 ± 29.33 vs.339.23 ± 162.30,P =0.018);and might have a lower classification of endomyocardial biopsy at 1st month (1.43 ± 0.73 vs.1.50 ± 0.58,P =0.867),3rd month (1.55 ±1.00 vs.2.00 ± 1.73,P =0.512),and 6th month (1.36 ± 0.84 vs.2.33 ± 1.53,P =0.132);as well as a higher mortality due to acute organ rejection (10％ vs.0,P =0.244) and all-cause mortality (20％ vs.9.7％,P =0.580).Conclusion In Chinese HTx recipients,the frequency of this * 3 allele is lower than that has been reported in the white population.The determinations of CYP3A5 genetypes in heart transplant recipients are helpful to guide the individualized Tac regimens.
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Objective To investigate the effect of CYP3A5 and C5 gene polymorphisms on the concentration/dose ratio of tacrolimus in Chinese liver transplant patients during the early posttransplantation period.Methods A total of 100 adult patients who underwent primary liver transplantation (LT) were enrolled.Tacrolimus dosage and trough blood concentration were detemined at first week after liver transplantation.Two single-nucleotide polymorphisms were genotyped and analyzed in both donor and recipient groups.The relationship between gene polymorphisms and tacrolimus concentration/dose ratio (C/ D ratio) was analyzed.Results The distribution of allele A in C5 rs17611 was 63.5 ％ among donors and 58.5％ among recipients.For CYP3A5,the rs776746 allele G represented the major alleles in both donors and recipients (71％ and 72％,respectively).The tacrolimus C/D ratio of recipients carrying allele AA in C5 rs17611 was significantly higher than that of recipients carrying the C5 rs17611 allele G.Both donor and recipient CYP3A5 rs776746 polymorphisms were highly correlated with the tacrolimus C/D ratio at first week after liver transplantation.No linkage disequilibrium between CYP3A5 rs776746 and C5 rs17611 polymorphisms was found (D'max =0.392,r2max =0.034).Recipient CYP3A5 rs776746 allele A,C5 rs17611 genotype AA,and donor CYP3A5 rs776746 allele A were associated with rapid tacrolimus metabolism.With increasing number of these alldes,tacrolimus C/D ratio was reduced during the one week after transplantation.Conclusion Recipient C5 rs17611 polymorphism is a new genetic locus that influences tacrolimus metabolism in patients after OLT during the early post-transplantation periocd.
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OBJECTIVE:To explore the difference of genotypes in patients with coronary artery disease(CAD)and different responses to clopidogrel. METHODS:Totally 159 CAD patients were selected from cardiology department of our hospital during Mar. 2013-Nov. 2015. They were given clopidogrel+aspirin for dual antiplatelet therapy for at least 1 year. Turbidimetry method was used to detect the percentage of platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA) before and after treatment. The polymorphism of cytochrome P450(CYP)2C19,CYP3A5,wild type leucine 33 allele(PLA1)/proline 33 al-lele(PLA2)were detected by PCR-RFLP. RESULTS:There were 3 kinds of CYP2C19 genotypes(2/2,2/1,1/1),3 kinds of CYP3A5 genotypes (3/3,3/1,1/1) and 3 kinds of PLA1/PLA2 genotypes (A1/A2,A2/A2,A1/A1);the frequency of each genotype was in line with Hardy-Weinberg balance(P>0.05). Among 159 cases,there were 81 cases of clopidogrelsemi-re-sponse,accounting for 50.9%;78 cases of clopidogrelresponse,accounting for 49.1%. The frequencies of CYP2C19 gene dele-tion(2/2 or 2/1 genotype)and 2 allele in clopidogrelsemi-responsepatients were significantly higher than clopidogrelre-sponsepatients,with statistical significance(P0.05). After treat-ment,the percentage of ADP or AA-induced platelet aggregation in different genotypes patients were significantly lowered,com-pared to before treatment;but the percentage of platelet aggregation in CYP2C19 gene deletion and CYP3A5 gene deletion patients were significantly higher than gene expression patients(1/1 genotype),with statistical significance(P0.05). CONCLUSIONS:The incidence of clopidogrelsemi-responsein CAD patients is high. CYP2C19 and PLA1/PLA2 gene polymorphism may be related to clopidogrelsemi-re-sponse,while CYP3A5 gene polymorphism has no relation-ship with it. CYP2C19 and CYP3A5 gene deletion may weaken inhibitory effects of clopidogrel on platelet aggregation of CAD patients.