CYP3A5 Single Nucleotide Polymorphisms Research Articles

Metabolic ratios and SNPs implicated in tramadol-related deaths.

Tramadol (TR) metabolism is performed by polymorphic enzymes that are influenced by genetic polymorphisms. Within this scope, the study presented here aimed to describe 41 genetic variants within CYP2D6, CYP2B6, and CYP3A4 genes in 48 cases of TR-related death that may be involved in the response to TR and to assess whether there is a correlation between these genetic variants and metabolic ratios (MRs). Blood samples from 48 victims of a TR-related death were analyzed to determine the concentrations of TR and its metabolites [O-desmethyltramadol (M1) & N-desmethyltramadol (M2)] using a LC-MS/MS method. All the samples were also genotyped for 41 common CYP2D6, CYP2B6, and CYP3A4 single nucleotide polymorphisms (SNPs) using the HaloPlex Target Enrichment system. Cases with the T/- genotype (rs35742686 in CYP2D6) had significantly higher M2/M1 ratio than cases with T/T genotype and cases with the G/A genotype (rs35599367 in CYP3A4) had significantly higher MR2 (TR/M2) ratio than cases with G/G genotype. The frequency of tested SNPs which belong to CYP2D6, CYP2B6, and CYP3A4 revealed the over-presentation of 2 SNPs (rs1058172 in CYP2D6 and rs4803419 in CYP2B6) in TR overdose group, which could have toxicological implications. These results indicate these polymorphisms in CYP2D6, CYP2B6, and CYP3A4 might influence the function and could increase the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.

Role of CYP19A1 Loci (rs28757157 and rs3751591) with Ischemic Stroke Risk in the Chinese Han Population.

Ischemic stroke (IS) is a multifactorial and polygenic disease, which is affected by genetic factors. In this study, we explored the role of CYP19A1 single nucleotide polymorphisms (SNPs) in IS in the Chinese population. 1302 subjects (651 controls and 651 cases) were recruited in this case-control study. Four candidate SNPs (rs28757157 C/T, rs3751592 C/T, rs3751591 G/A, rs59429575 C/T) of CYP19A1 were selected by the 1000 genomes project database. The association between CYP19A1 SNPs and IS risk was assessed using logistic regression analysis with odds ratio (OR) and 95% confidence intervals (CIs). False-positive report probability (FPRP) analysis further verified the positive results. The interaction of SNP-SNP was analyzed by multi-factor dimensionality reduction (MDR) to predict is risk. In the research, CYP19A1 loci (rs28757157 and rs3751591) were associated with the occurrence of IS. The two variants conferred an increased susceptibility to IS in the subjects aged over 60 years old, smokers and drinkers. Rs28757157 was related to the risk of IS in females, non-smokers and subjects with BMI less than 24, while rs59429575 was related to the risk of IS in males and subjects with BMI greater than 24. The study revealed that there is a significant association between CYP19A1 loci (rs28757157 and rs3751591) and IS risk in the Chinese Han population, providing a theoretical basis for further exploring its specific role in the pathogenesis of IS.

Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56–0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65–0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk.

Evaluation of Pharmacogenetics of Drug-Metabolizing Enzymes and Drug Efflux Transporter in Renal Transplants Receiving Immunosuppressants.

Cytochrome P450 (CYP) enzymes, such as CYP3A4, and CYP3A5, P450 oxidoreductase (POR), peroxisome proliferator activated receptor alpha (PPAR-alpha), and drug transporter (ABCB1) were observed to influence concentrations of immunosuppressants (cyclosporine, everolimus, sirolimus, and tacrolimus) and outcomes in renal transplants. We carried out the present study to evaluate the prevalence and impact of these single nucleotide polymorphisms (SNPs) in adult renal transplants. SNPs were evaluated using commercial TaqMan® assays. Serum drug concentrations were estimated using immunoassays. One hundred and forty-six patients were recruited. SNPs in CYP3A5*3 were significantly associated with greater dose-adjusted cyclosporine and tacrolimus concentrations. SNPs in POR*28 were observed with significantly lower dose-adjusted concentrations, particularly with cyclosporine and tacrolimus. ABCB1 homozygous polymorphisms were observed with significantly lower time spent in the therapeutic range with cyclosporine and everolimus/sirolimus. Cyclosporine was observed in a significantly greater proportion of patients with elevated GGT, and SNPs in PPAR-alpha were significantly associated with an increased risk of this adverse event. Hypertriglyceridemia with everolimus was significantly associated with POR*28 polymorphisms. There is a need to validate the influence of these SNPs in a prospective study and develop an algorithm predicting the achievement of target concentrations.

Computational validation of ABCB1 gene polymorphism and its effect on tacrolimus dose concentration/levels in renal transplant individuals of South India

Patients with end-stage renal failure require hemodialysis and peritoneal dialysis; however, kidney transplantation is considered a better treatment option for renal failure patients, improving their quality of life and longevity. Among several potent immunosuppressive agents, tacrolimus (TAC) has shown progressive improvement in the graft survival rates after renal transplantation. Fifty kidney transplant patients undergoing TAC immunosuppressive treatment were included. The human genomic DNA was isolated using the phenol-chloroform extraction procedure. CYP3A5*6, CYP3A5*2, and ABCB1 exon 21 G2677 T/A polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Fisher's exact test and Chi-square analysis were performed to analyze the data, where p < 0.05 was considered statistically significant. In addition, we implemented bioinformatics studies on ABCB1 protein to determine the mutation's effect sequentially and structurally. Among the genotyped single nucleotide polymorphisms (SNPs), SNPs of CYP3A5*2 and CYP3A5*6 did not vary in the studied population. The concentration/dose (C/D) ratio of TT genotype of the ABCB1 gene was higher (95% CI: 177.38–269.46) when compared to TA and AA. However, there were no substantial differences between the ABCB1 genotypes and TAC C/D ratio (p = 0.953). The TAC dose mg/kg/day (p = 0.002) and C/D ratio (p = 0.004) exhibited a statistically significant difference. However, no significant difference was found with respect to the ABCB1 gene between the non-toxicity and toxicity groups. Mutation and residue interaction analysis results showed that the S893T mutation destabilizes the ABCB1 protein, thus reducing the protein's flexibility. The present study demonstrated a substantial relationship between the TAC dose and C/D ratio, including the non-toxicity and toxicity groups. However, no possible correlation was observed between the ABCB1 gene polymorphism and renal transplant.

Association of CYP19A1 and CYP1A2 genetic polymorphisms with type 2 diabetes mellitus risk in the Chinese Han population

BackgroundType 2 diabetes mellitus (T2DM), one of the global health issues, is a group of metabolic diseases and is affected by several genetic loci in the clinical phenotype. This study intended to ascertain associations between CYP19A1 and CYP1A2 gene polymorphisms with the T2DM risk in Chinese Han.MethodsSeven single nucleotide polymorphisms (SNPs) in total including five of CYP19A1 (rs4646, rs6493487, rs1062033, rs17601876 and rs3751599) and two of CYP1A2 (rs762551 and rs2470890) from 512 T2DM patients and 515 non-diabetic controls were genotyped in the platform of Agena MassARRAY. SPSS 18.0 was utilized for analyzing genotyping results. Logistic regression models were conducted for the risk assessment by the odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe results suggested a significant association between genotype GC of rs1062033 with a decreased T2DM risk (OR = 0.73, 95% CI = 0.55–0.96, P = 0.025) under the co-dominant (heterozygous) model. The results of stratification analysis with age and gender adjustment revealed that the effects of all selected SNPs in CYP19A1 and CYP1A2 on the T2DM susceptibility were dependent on age, body mass index (BMI) and disease progression (P < 0.05). The haplotype analysis was further conducted and the results indicated that Crs1062033Grs17601876Ars3751599 in CYP19A1 played a protective role (OR = 0.48, 95% CI = 0.25–0.91, P = 0.026) in T2DM patients with diabetic retinopathy.ConclusionThis population-based case-control study suggested that CYP19A1 and CYP1A2 variations might affect the susceptibility of T2DM. The findings provide a theoretical basis for searching the clinical therapeutic markers and attractive drug targets of T2DM.

Recent advances in precision medicine for individualized immunosuppression.

The current tools to proactively guide and individualize immunosuppression in solid organ transplantation are limited. Despite continued improvements in posttransplant outcomes, the adverse effects of over-immunosuppression or under-immunosuppression are common. The present review is intended to highlight recent advances in individualized immunosuppression. There has been a great focus on genomic information to predict drug dose requirements, specifically on single nucleotide polymorphisms of CYP3A5 and ABCB1. Furthermore, biomarker studies have developed ways to better predict clinical outcomes, such as graft rejection. The integration of advanced computing tools, such as artificial neural networks and machine learning, with genome sequencing has led to intriguing findings on individual or group-specific dosing requirements. Rapid computing allows for processing of data and discovering otherwise undetected clinical patterns. Genetic polymorphisms of CYP3A5 and ABCB1 have yielded results to suggest varying dose requirements correlated with race and sex. Newly proposed biomarkers offer precise and noninvasive ways to monitor patient's status. Cell-free DNA quantitation is increasingly explored as an indicator of allograft injury and rejection, which can help avoid unneeded biopsies and more frequently monitor graft function.

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

Abstract P5-06-30: Identification of novel single nucleotide polymorphisms located in MAP3K1 and ABCB1 genes as markers for poor overall survival in early-stage hormone receptor-positive breast cancer using next-generation sequencing

Abstract Background: We previously revealed that single nucleotide polymorphisms (SNPs) of CYP19A1, MAP3K1 rs889312, and ABCB1 rs2032582 were associated with overall survival (OS) in early-stage hormone receptor (HR)-positive breast cancer patients. Previous studies also showed that FGFR2 rs1219468 and TOX3 rs8051542 influenced OS in early-stage breast cancer patients. In this study, we assessed whether undiscovered SNPs of CYP19A1, MAP3K1, ABCB1, FGFR2, and TOX3 are associated with clinical outcome of patients with early-stage HR-positive breast cancer. Patients and Methods: We used next-generation sequencing (NGS) methods to explore unidentified SNPs of CYP19A1, MAP3K1, ABCB1, FGFR2, and TOX3 in 80 patients who had HR+, T1 to T2, and N0 to N1 breast cancer and had matched clinicopathological features and clinical outcomes (experimental cohort). The mapping selected SNPs identified from NGS were located in different chromosomes, such as chromosome 5 (MAP3K), 7 (ABCB1), 10 (FGFR2), 15 (CYP19A1), and 16 (TOX3), were analyzed. The multivariate-adjusted hazard ratio (aHR) of OS associated with the individual genotypes of the experimental cohort was assessed after adjusting for age, tumor size, tumor grade, HER2 status, menopausal status, and chemotherapy using Cox regression analyses. We further correlated identified significant novel SNPs with disease-free survival (DFS) and OS in 195 patients with HR-positive, T1-T2, and N0-1 breast cancer (validation cohort) using stepwise selection multiple Cox model analyses. Results: Through target region re-sequencing, we identified 69 novel SNPs, including 18 CYP19A1 SNPs, 16 MAP3K SNPs, 18 ABCB1 SNPs, 12 FGFR2 SNPs, and 5 TOX3 SNPs in the experimental cohort (n = 80). After multivariate-adjusted analyzing, FGFR2 rs2981460(C/C) (p = 0.0115), and MAP3K1 rs3822625 (A/A) (p = 0.0475), rs702689 (G/G) (p = 0.0312), rs832567 (C/C) (p = 0.0312), and rs9687226 (C/C) (p = 0.0475), and ABCB1 rs2032582 (T/T+T/C) (p = 0.0061) were significantly associated with the poorer OS of the experimental cohort. In a validated cohort (n =195) (Table 1), we found that MAP3K1 rs702689 (G/G) was significantly associated with poorer DFS (aHR = 2.3; 95% confidence interval [CI] = 1.1 to 5.1; p = 0.03) and OS (aHR = 4.9; 95% CI = 1.3 to 18.7; p = 0.02). In addition, MAP3K1 rs832567 (C/C) was significantly associated with poorer DFS (aHR = 2.5; 95% CI = 1.1 to 5.5; p = 0.02) and OS (aHR = 5.4; 95% CI = 1.4 to 21.6; p = 0.02). In premenopausal women of validation cohort (n = 108), ABCB1 rs2032582 (T/T+T/C) was significantly associated with a poor OS (aHR = 62.3; 95% CI = 2.0 to 1911.7; p = 0.02). Conclusions: Our results indicate that 3 novel SNPs, MAP3K1 rs702689, MAP3K1 rs832567, and ABCB1 rs2032582, may affect the prognosis of early-stage HR-positive breast cancer. Further validation of these SNPs in a large series of patients with early-stage HR-positive breast cancer who received adjuvant endocrine therapy alone is warranted. Table 1. The Associations of Hormone Receptor-Positive Breast Cancer Patients with Various Genotypes in multiple Cox model (validation cohort)Disease-free survivalOverall survivalGenotypeaHR (95%CI)PaHR (95%CI)PTotal (n = 195)FGFR2_ rs2981460 (C/C vs.C/T+T/T)0.4 (0.1-1.8)0.220.6 (0.1-5.4)0.68MAP3K1_ rs3822625 (A/A vs. G/A+GG)2.0 (0.7-5.3)0.192.7 (0.6-12.9)0.20MAP3K1_ rs702689 (G/G vs. A/A+A/G)2.3 (1.1-5.1)0.034.9 (1.3-18.7)0.02MAP3K1_rs832567 (C/C vs. A/A+A/C)2.5 (1.1-5.5)0.025.4 (1.4-21.6)0.02MAP3K1_rs9687226 (C/C vs. T/T+T/C)2.0 (0.7-5.3)0.192.7 (0.6-12.9)0.20Premenopausal (n=108)ABCB1_rs2032582 (T/T+T/C vs. C/C)2.0 (0.8-5.0)0.1562.3 (2.0-1911.7)0.02aHR: adjusted by age, estrogen receptor and progesterone receptor status, number of lymph nodes, menopausal status, adjuvant chemotherapy, lymphovascular invasion, and tumor size. Citation Format: Sung-Hsin Kuo, Shi-Yi Yang, Po-Han Lin, Chen-Hsin Chen, Hsin-Chou Yang, Chih-Yuan Hsu, Chiun-Sheng Huang. Identification of novel single nucleotide polymorphisms located in MAP3K1 and ABCB1 genes as markers for poor overall survival in early-stage hormone receptor-positive breast cancer using next-generation sequencing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-30.

Melding Pharmacogenomic Effect of MDR1 and CYP3A5 Gene Polymorphism on Tacrolimus Dosing in Renal Transplant Recipients in Northern India

IntroductionTacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The Multidrug resistance gene 1 (MDR1) and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited.MethodsThe daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), MDR1 at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the MDR gene and CYP3A5 for optimized TAC levels.ResultsAmong CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A5*1*1 (expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the MDR1 gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A5*3*3 and wild-type GG of the G2677T/A genotype.ConclusionBoth CYP gene and MDR1 gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.

SUN-115 Personalised Pharmacogenomics of Tacrolimus in Renal Transplantation- Indian Experience

Tacrolimus has a narrow therapeutic index with high intra and inter individual pharmacokinetic variability. Tacrolimus is metabolized by Cytochrome P450 (CYP) 3A enzymes specifically 3A4 and 3A5 in small intestine, liver and in kidney. Single Nucleotide Polymorphisms of CYP3A5 can result in changes to the activity of CYP3A5 . Caucasians commonly have a Non Expressor status of CYP3A5 (CYP3A5 GG) and have vastly reduced dosing requirements compared to Expressor status (CYP3A5 AA/AG). We studied the CYPA4 Expression status in Indian Patients.

The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients.

Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients.We aim to investigate the effects of cytochrome P450 (CYP)3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6months after heart transplantion to evaluate acute rejection degrees. All participants were then followed upannually until May 2018.The designed primary endpoint was all-cause mortality. In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6months after heart transplantion. The median follow-up period was 94.7months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis.

Background/AimsThe 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. MethodsTwenty-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).ResultsThe 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.ConclusionsIndividualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype.

Impact of CYP3A4 and CYP3A5 single nucleotide polymorphisms on anastrozole-associated adverse events among Malaysian breast cancer patients

The catalytic activity of the cytochrome P450A (CYP3A4) enzyme is reportedly affected by the presence of single nucleotide polymorphisms (SNPs), leading to inter-individual variability in drug efficacy and adverse reactions. CYP3A4 polymorphisms can serve as potential biomarkers for predicting the efficacy of many drugs, including those used in breast cancer treatment. This study was conducted on 94 hormone receptor-positive postmenopausal breast cancer patients who received 1 mg of anastrozole per day. Anastrozole-associated adverse events (AAAEs), such as musculoskeletal adverse events (MSAEs), hot flashes, mood disturbance and vaginal dryness/dyspareunia, were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed to determine the allelic frequency of CYP3A4*4, CYP3A4*18A, CYP3A4*18B, CYP3A4*22 and CYP3A5*3. The frequencies of CYP3A4*18A T&gt;C (rs28371759), CYP3A4*18B G&gt;A (rs2242480) and CYP3A5*3 were 0.03, 0.48 and 0.64, respectively. However, no CYP3A4*4 A&gt;G (rs55951658) or CYP3A4*22 C&gt;T (rs35599367) alleles were detected. No significant association was observed between the alleles and the development of AAAEs. We have demonstrated for the first time that CYP3A4*18B G&gt;A is highly prevalent among Malaysian breast cancer patients. The clinical relevance of CYP3A4*18B is currently under investigation by our group.

Frequencies of CYP1A2 Single Nucleotide Polymorphism in Indonesian and Its Effect on Blood Pressure

BACKGROUND: The association between caffeine with blood pressure (BP) still remains controversial. Caffeine is mainly metabolized by cytochrome-P450 (CYP)1A2 enzyme. Polymorphism of CYP1A2 is known to cause interindividual variation on enzymatic activity, thus affects caffeine metabolism and its effect on cardiovascular (CV) system.METHODS: We conducted a cross-sectional study and recruited 121 Indonesian subjects aged 25-60 years with varying coffee-drinking habits. DNA was extracted from peripheral blood and genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) technique. Blood pressures were measured in the morning prior to the daily activity. Caffeine concentration in blood plasma was measured using high-performance liquid chromatography (HPLC). The differences between variables were analyzed using MannWhitney analysis and the correlations among variables were determined using multivariate logistic regression analysis.RESULTS: This study showed that the frequencies of single nucleotide polymorphisms (SNPs) among Indonesian were 31.8%, 18.2%, 25.2% and 24.8% respectively for CYP1A2*1A, CYP1A2*1B, CYP1A2*1C and CYP1A2*1F alleles. The genotype analysis showed that the subject number of the wild type (*1A/*1A) and the variants were 9.92% and 90.08%. There were no significant differences in term of BP levels among CYP1A2 genotypes and coffee drinking habit groups.CONCLUSIONS: The frequencies of CYP1A2 SNPs in Indonesian are different with frequencies in other populations. Since the association were not statistically significant, CYP1A2 polymorphisms as the predictor of elevated blood pressuare should be investigated further.KEYWORDS: coffee, caffeine, blood pressure, single nucleotide polymorphism, CYP1A2

Influence of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics/Pharmacodynamics of Tacrolimus in Pediatric Patients.

Single Nucleotide Polymorphisms (SNPs) are very common variants of many genes and are also promising markers associated with drug reactions in pharmacogenomics research. In pediatric organ transplantation, tacrolimus is a major immunosuppressive agent used to prevent organ rejection. The SNP of these genes have been studied extensively in adult population, but there is no systematic review in children. This article focuses on the effects of ABCB1 and CYP3A SNPs on tacrolimus in children who are undergoing organ transplantations. We searched the literature that provided the effect of SNP on metabolism and pharmacokinetics of tacrolimus in pediatric patients in Google, Science Direct and PubMed. Then we accessed the methods used in these studies, the sample size, the model and the conclusions they have obtained. We found that there is no evidence shown that CYP3A4 SNP has an influence on the pharmacokinetic/ pharmacodynamics of tacrolimus in the population of children. Moreover, most studies have failed to find a link between the ABCB1 SNP and the pharmacokinetics of tacrolimus in children. However, although the amount of literature is limited, it does show a link between ABCB1 SNPs and tacrolimus pharmacodynamics. In addition, the literature shows a strong link between CYP3A5 SNP and pharmacokinetics of tacrolimus, but there is no direct evidence that CYP3A5 SNP has the same effect on the pharmacodynamics of tacrolimus. More standardized clinical trials are needed to assess the relationship between CYP3A5 SNP and tacrolimus pharmacodynamics in children, particularly in terms of acute rejection and nephrotoxicity.

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C0 /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1±1.6days for CYP3A extensive metabolizers (EM, P<0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2±0.5days less (P=0.01) and EM spent 2.1±0.5days less (P<0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C0 /D (P<0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P=0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P=0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

Increase in tacrolimus exposure after steroid tapering is influenced by CYP3A5 and pregnane X receptor genetic polymorphisms in renal transplant recipients.

Tacrolimus, a drug for prevention of rejection after kidney transplantation, has a narrow therapeutic window and is metabolized by the cytochrome P540 3A (CYP3A) system. Tacrolimus exposure increases after steroid tapering in many patients. The pregnane X receptor (PXR)-a mediator for CYP3A-has a steroid receptor and might regulate CYP3A5 activity depending on single nucleotide polymorphisms (SNPs) of CYP3A5 or PXR. This may contribute to differences in tacrolimus exposure after steroid tapering. In a cohort of renal transplant recipients, the influence of CYP3A5 and PXR SNPs (A7635G, C8055T and C25385T) on the dose-normalized Tacrolimus trough concentration (DnC0) and their potential interaction with each other after steroid taper were analysed by linear regression. Eligible were all 83 outpatient renal transplant patients on tacrolimus and steroids in a pharmacokinetic steady state at least 6 weeks after transplantation and whose blood was available for genetic analysis. Compared with the CYP3A5*1/*3 genotype, the CYP3A5*3/*3 SNP showed a significantly stronger increase in DnC0 after steroid taper (+0.29 µg/L/mg; P = 0.002). Of the tested PXR SNPs, PXR G7635G individuals had a significantly stronger increase in DnC0 (compared with A7635A, +0.31 µg/L/mg; P = 0.02), with a weaker increase in A7635G heterozygotes (+0.17 µg/L/mg; P = 0.124). There was neither interaction nor association between CYP3A5 and PXR SNPs. The magnitude of the DnC0 increase due to steroid taper after renal transplantation is related to CYP3A5 SNPs. Independently, the PXR G7635G SNP is related to this increase, proving the role of PXR in tacrolimus metabolism.

Association of Measures of Muscle Density and SNPs in Homologs of Muscle Function Genes in C.elegans

Sarcopenia, the loss of muscle mass and strength that occurs with aging, has a crucial role in development of frailty. Although sarcopenia and other muscle-related traits are heritable, the underlying genetic variation contributing to the development of sarcopenia is unclear. Our aim was to assess whether there is a relationship between >700 single nucleotide polymorphisms (SNPs) total in 27 genes (14 genes identified from C. elegans and 13 genes in the mevalonate and ubiquinone pathways) and six traits related to sarcopenia using data from the HealthABC cohort. No SNPs were statistically significant at the experiment-wide p-value (p< 0.00001). SNPs in the locus MAGOHB were associated with THIMF, THMUSD, and TOTPF in European Americans, whereas SNPs in CYP3A5 were associated with these traits in African Americans (p<0.01 for all). Furthermore, SNPs in GOLGA4 (P<0.01) and RALGABP (P<0.001) were associated with TOTPF in African Americans, and SNPs in RALGABP were also associated with THIMF and TOTLEAN in African Americans. The results indicate that variation in some genes related to development of muscle-wasting in an animal model, C.elegans , may have pleiotropic effects on traits related to sarcopenia in older men and women. Keywords: Sarcopenia, C.elegans, association, Health ABC

SLCO1B1 521T>C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study.

This nested case-control study aimed to evaluate the association of candidate genetic variants with statin-induced myotoxicity in Chinese patients with coronary artery disease (CAD). One hundred forty-eight Chinese patients experiencing statin-induced myotoxicity were included in our study, and 255 patients without muscular side effects served as controls. Five SNPs in CYP3A5, SLCO1B1, and APOE were genotyped. The effect of genetic variants on statin-induced myotoxicity was assessed. Patients who carried at least one SLCO1B1 521C allele had a higher risk for myotoxicity (OR=1.69, 95%CI=1.07-2.67, P=0.024). Significant association was found between SLCO1B1 521C mutant allele mutation and risk of myotoxicity in individuals that received rosuvastatin (OR=3.67, 95%CI=1.42-9.47, P=0.007). However, non-significant association was observed between 521C mutant allele and risk of myotoxicity (P>0.5) in patients that received atorvastatin and simvastatin. The other four single nucleotide polymorphisms (SNPs), namely rs776746, rs2306283, rs7412, and rs429358, showed no significant association with any statin induced myotoxicity (P>0.5). SLCO1B1 (rs4149056, 521T>C) is associated with statin-induced myotoxicity in Chinese patients with coronary artery disease. In addition, SLCO1B1 521C mutant allele increased the risk of rosuvastatin-associated myotoxicity.