CYP3A5 Rs776746 Research Articles

Effect of donor GSTM3 rs7483 genetic variant on tacrolimus elimination in the early period after liver transplantation.

Glutathione S-transferase mu (GSTM) belongs to the group of phase II drug-metabolizing enzymes, and the GSTM1 genetic variant has been reported to have a potential association with the metabolism of immunosuppressive drug after renal transplantation. The effect of donor and recipient GSTMs genetic variants on tacrolimus (Tac) metabolism was the focus of our investigation in this study. A total of 203 liver transplant patients were recruited for the study. In the training set (n=110), twenty-one SNPs in five genes (GSTM1-5) were genotyped by the drug-metabolizing enzymes and transporter (DMET) microarray. CYP3A5 rs776746 and GSTM3 rs7483 were genotyped using a Mass ARRAY platform in the validating set (n=93). Tac C/D ratios of donor GSTM3 rs7483 AA carriers were significantly lower than those with the G allele at weeks 1, 2, 3 and 4 after liver transplantation (LT). Multivariate analysis was conducted on the training set and validating set, donor and recipient CYP3A5 rs776746, donor GSTM3 rs7483 and total bilirubin were identified as independent predictors of Tac C/D ratios in the early period after LT. Combining CYP3A5 rs776746 and donor GSTM3 rs7483 genotypes, Tac C/D ratios were observed to be increasingly lower with increasing numbers of alleles associated with fast metabolism. Moreover, the risk of a supratherapeutic C0 (Tac > 15 ug/L) was significantly higher for poor metabolizers than the other groups at week 1 after LT. There was a significant association between the donor GSTM3 rs7483 genetic variant and Tac metabolism in the early period after LT. Genotype classification might have a better predictive ability of the initial Tac doses.

Bleeding Events Associated with Rivaroxaban Therapy in Naive Patients with Nonvalvular Atrial Fibrillation: A Longitudinal Study from a Genetic Perspective with INR Follow-Up.

Background and Objectives: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods: The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results: The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions: It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.

Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.

Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients.

Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome. 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the CYP3A5 rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years. CYP3A5 expression was detected in 33 (21%) of the 160 patients. Tacrolimus trough levels were similar in CYP3A5 expressers and nonexpressers over the entire 2-year follow-up period. However, we observed a trend toward slightly higher tacrolimus trough levels in CYP3A5 expressers, who, as expected, required tacrolimus dosages twice as high as did nonexpressers during follow-up. Calcineurin inhibitor (CNI) nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and nonexpressers (p = 0.49). Rejection-free survival rates (p = 0.89), de novo anti-HLA antibody-free survival rates (p = 0.57) and de novo DSA-free survival rates (p = 0.61) did not differ between the two groups. Early detection of CYP3A5-expression status and resultant genotype-based adjustment of tacrolimus dosage after renal transplant protected patients from transplant rejection and de novo DSA formation and was not associated with increased incidence of CNI toxicity among CYP3A5 expressers.

Influence of Genetic Polymorphisms on the Age at Cancer Diagnosis in a Homogenous Lynch Syndrome Cohort of Individuals Carrying the MLH1:c.1528C>T South African Founder Variant.

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini-Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01-4.08], p = 0.034 and Adj HR: 1.53 [1.09-2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48-0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06-2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37-0.73], and Adj HR: 0.51 [CI: 0.36-0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene.

Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose

In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.

FEATURES OF DRUG-DRUG INTERACTIONS BETWEEN RIVAROXABAN AND P-GLYCOPROTEIN INHIBITOR DEPENDING ON CYP3A4/A5 GENE POLYMORPHISM IN PATIENTS 80 YEARS AND OLDER WITH NONVALVULAR ATRIAL FIBRILLATION

Abstract Introduction. Increased risk of bleeding associated with rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs that inhibit common metabolic pathways. However, the data are contradictory. Objective of the work.To study the features of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor (using verapamil as an example) depending on the polymorphism of the CYP3A4 (rs35599367)and CYP3A5 (rs776746)genes in patients aged 80 years and older with non-valvular atrial fibrillation. Material and methods. A total of 128 patients (median age 87.5 years [83-90 years], 75% women) were examined. All patients underwent genotyping for the studied polymorphisms, determination of the minimum steady-state concentration of rivaroxaban (Cmin,ss), standardization of the minimum steady-state concentration of rivaroxaban per daily dose (Cmin,ss /D), determination of prothrombin time (PT) in plasma, and analysis of medical records for the presence of clinically relevant non-major bleeding (CRNMB). Results.Co-administration of rivaroxaban with verapamil compared with patients receiving rivaroxaban without calcium channel blockers in CYP3A4gene CC carriers resulted in higher values of Cmin,ss(73.8 [49-113.5] vs 40.5 [25.6-73.3] ng/ml), Cmin,ss /D (2.5 [1.7-4.0] vs 4.7 [2.9-7.7] ng/ml/mg), PT (14.8 [13.3-17.3] vs 14.0 [12.6-14.5] sec) and CRNMB (10/30 (33.3%) vs 6/45 (13.3%) cases), (p0.05). In carriers of the GG gene, CYP3A5resulted in higher values of Cmin,ss (74.7 [50.6-108.8] vs 40.2 [25.7-72.3] ng/ml), Cmin,ss /D 4.6 [3.0-7.3] vs 2.5 [1.7-4.0] ng/ml/mg), PT (14.6 [12.8-15.2] vs 14.0 [12.6-14.5] sec) and CRNMB (10/27 (37%) vs 5/40 (12.5%) cases), (p0.05). And in GA+AA carriers of the CYP3A5gene, it resulted in higher values of Cmin,ss (88.1 [5.5-88.1] vs 52.8 [25.0-77.2] ng/ml), Cmin,ss /D 5.7 [0.4-5.7] vs 3.5 [1.7-5.2] ng/ml/mg), (p0.05). In CT carriers of the CYP3A4 gene, the combined use of rivaroxaban with verapamil was not observed in our sample. Conclusions:Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).

Peripheral pathway gene variants in lifelong premature ejaculation: CYP19A1, CYP1A1, and CYP1A2 enzymes polymorphisms in Chinese Han men

Abstract Background Recent genetic association studies focusing on central pathways have been performed to investigate the correlation between susceptibility alleles and the risk of lifelong premature ejaculation (LPE). However, there remains a dearth of documented genes associated with peripheral pathways. Objective In this study we aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) associated with the peripheral genes CYP19A1, CYP1A1, and CYP1A2 and the risk of LPE. Methods From August 2017 to August 2020, a total of 511 participants (139 LPE patients and 372 controls) were recruited. Trained medical professionals diagnosed LPE according to the standard definition set by the International Society for Sexual Medicine. Nine candidate SNPs were chosen and genotyped using the MassARRAY system. Allele and genotype frequencies of the SNPs among patients and controls were compared using the χ2 test. Logistic regression analysis, adjusted for age, was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using PLINK version 1.9. Haploview software was employed to analyze linkage disequilibrium and haplotype distribution. The interaction among candidate SNPs concerning LPE risk was evaluated using multifactor dimensionality reduction. The relationship between selected polymorphisms and specific features was assessed using analysis of variance. Outcome Heterozygous SNPs located in the CYP19A1 (rs4646, rs17601876), CYP1A1 (rs1048943), and CYP1A2 (rs762551, rs2470890) genes showed significant correlations with the risk of LPE. Results The findings of this study confirmed that heterozygous SNPs in the CYP19A1 (rs4646 AC vs CC: OR, 1.84; CI, 1.10-3.09; rs17601876 AG vs GG: OR, 1.80; CI, 1.06-3.05) and CYP1A1 genes (rs1048943 CT vs TT: OR, 1.71; CI, 1.02-2.87), respectively, can significantly increase the LPE risk. Participant scores for the Premature Ejaculation Diagnostic Tool (P =.002) and International Index of Erectile Function-5 (P =.020) differed significantly by genotype for the different genotypes of CYP1A1-rs1048943. Haplotype analysis revealed strong linkage disequilibrium under CYP1A2_rs762551-rs2470890 (D' = 1.00). Clinical Implications The findings of this and other investigations of genetic determinants and potential pathogenic mechanisms of LPE may advance diagnostic and therapeutic opportunities in LPE patients. Strengths and Limitations In this study of LPE in men with CYP gene variants we addressed a current research gap. However, data on risk factors such as smoking and drinking were incomplete in both the case and control groups. In future studies we will expand the sample size and enhance data on risk factors for more precise assessments. Conclusion In summary, polymorphisms in the peripheral genes CYP19A1, CYP1A1, and CYP1A2 may play a role in LPE among Chinese men of the Han population.

Unraveling the molecular significance of CYP1A2 (rs762551; c.-9–154 C>A) genetic variant on breast carcinoma susceptibility: Insights from case-control study and meta-analysis

BackgroundThe human cytochrome P450 (CYP) superfamily encompasses different categories of isoenzymes that contribute to multiple metabolic processes involving drug detoxification, cellular signaling, and the proliferation of malignant tissues. Using genetic technology, customized bioinformatic analysis, and meta-analysis design, the main goal of this study was to identify the association between the CYP1A2*rs762551 variant and the susceptibility to breast carcinoma (BRCA). MethodsThe case-control study was conducted based on 104 BRCA women and 102 healthy controls. Using the TaqMan allelic discrimination assay, the CYP1A2 (rs762551; c.–9–154 C>A) variant was genotyped. Bioinformatic frameworks and logistic regression analysis were used to assess the involvement of this genetic variant in BRCA development. A meta-analysis design was accomplished based on our case-control study and other previously published records. Publication bias, heterogeneity between studies, and trial sequential analysis (TSA) were analyzed. ResultsThe CYP1A2*rs762551 variant conferred protection against BRCA development under allelic (OR = 0.48, p-value < 0.001), dominant (OR = 0.34, p-value < 0.001), and recessive (OR = 0.44, p-value = 0.011) models. However, this intronic variant was correlated with a decreased risk of BRCA among late-onset menopause women compared to other cases. Bioinformatic analysis confirmed that this genetic variant has a functional impact on the progression of tumorgenesis. Moreover, this meta-analysis design included 12922 BRCA women and 15603 healthy controls. Our findings disclosed the contribution of the CYP1A2*rs762551 variant with protection against cancer development among Caucasian females under allelic (OR = 0.75, p-value = 0.025), and dominant (OR = 0.58, p-value = 0.015) models. ConclusionsThis case-control study confirmed the contribution of the CYP1A2*rs762551 variant with decreased risk of BRCA development among Egyptian subjects. Moreover, BRCA women with late-onset menopause conferred protection against cancer progression compared to other subjects. Our findings identified that this meta-analysis design achieved protection against BRCA development among Caucasian women compared to other ethnicities.

Exploring the relationship between caffeine metabolism-related CYP1A2 rs762551 polymorphism and team sport athlete status and training adaptations

BackgroundThis study aimed to achieve a dual objective: to compare the frequencies of CYP1A2 rs762551 genotypes between team sport athletes and a control group, and to determine the association between the rs762551 polymorphism and changes in physical performance after a six-week training program among elite basketball players.MethodsThe study encompassed an analysis of 504 individuals, comprising 320 athletes and 184 controls. For the Turkish cohort, DNA was isolated using the buccal swab method, and genotyping was conducted using the KASP technique. Performance assessments included the Yo-Yo IR2 and 30 m sprint tests. For Russian participants, DNA samples were extracted from peripheral blood, a commercial kit was used for DNA extraction, and genotyping of the rs762551 polymorphism was conducted using DNA microarray.ResultNotably, a statistically significant linear decline in the prevalence of the CC genotype was observed with ascending levels of athletic achievement within team sports (sub-elite: 18.0%, elite: 8.2%, highly elite: 0%; p = 0.001). Additionally, the CA genotype was the most prevalent genotype in the highly elite group compared to controls (80.0% vs. 45.1%, p = 0.048). Furthermore, statistically significant improvements in Yo-Yo IR2 performance were noted exclusively among basketball players harboring the CA genotype (p = 0.048).ConclusionsThe study’s findings indicate that the rs762551 CC genotype is a disadvantage in elite team sports, whereas the CA genotype provides an advantage in basketball performance.

Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Semi-physiological Pharmacokinetic Model of Clozapine and Norclozapine in Healthy, Non-smoking Volunteers: The Impact of Race and Genetics.

Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography-ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism. A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis. This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials.

The impact of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms on apixaban trough concentration and bleeding risk in patients with atrial fibrillation.

Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of CYP3A4*22, CYP3A5*3 and ABCB1 polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding. A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 μmol/L, F(1)=6.7, p=0.01124). ABCB1 (rs1045642 and rs4148738), CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding. We report no significant association between ABCB1 gene polymorphisms (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.

CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone.

Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs. Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism. The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05). The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.

Impact of CYP2C19, CYP2C9, CYP3A4, and FMO3 Genetic Polymorphisms and Sex on the Pharmacokinetics of Voriconazole after Single and Multiple Doses in Healthy Chinese Subjects.

Voriconazole is the first-line treatment for invasive aspergillosis. Its pharmacokinetics exhibit considerable inter- and intra-individual variability. The purpose of this study was to investigate the effects of CYP2C19, CYP2C9, CYP3A4, and FMO3 genetic polymorphisms and sex on the pharmacokinetics of voriconazole in healthy Chinese adults receiving single-dose and multiple-dose voriconazole, to provide a reference for its clinical individualized treatment. A total of 123 healthy adults were enrolled in the study, with 108 individuals and 15 individuals in the single-dose and multiple-dose doses, respectively. Plasma voriconazole concentrations were measured using a validated LC-MS/MS method, and pharmacokinetics parameters were calculated using the non-compartmental method with WinNonlin 8.2. CYP2C19, CYP2C9, CYP3A4, and FMO3 single-nucleotide polymorphisms were sequenced using the Illumina Hiseq X-Ten platform. The results suggested that CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of voriconazole at single doses of 4, 6, and 8 mg/kg and multiple doses of voriconazole. CYP3A4 rs2242480 had a significant effect on AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity) and MRT (mean residence time) of voriconazole at a single dose of 4 mg/kg in CYP2C19 extensive metabolizer. Regardless of the CYP2C19 genotype, CYP2C9 rs1057910 and FMO3 rs2266780 were not associated with the pharmacokinetics of voriconazole at three single-dose levels or multiple doses. No significant differences in most voriconazole pharmacokinetics parameters were noted between male and female participants after single and multiple dosing. For patients receiving voriconazole treatment, CYP2C19 genetic polymorphisms should be genotyped for its precision administration. In contrast, based on our study of healthy Chinese adults, it seems unnecessary to consider the effects of CYP2C9, CYP3A4, and FMO3 genetic polymorphisms on voriconazole pharmacokinetics.

Impact of CYP3A4 rs2242480 polymorphisms on Imatinib HPLC determined trough concentration and response in Chronic Myeloid Leukaemia in Pakistani patients

Objective To ascertain the impact of CYP3A4 polymorphism on the therapeutic outcome of imatinib and its trough concentration Study design Descriptive analytical study Place and duration of the study This study was conducted in the Department of Pharmacology &amp; Therapeutics, Islamic International Medical College, between December 2020 and February 2022, in collaboration with the Institute of Biomedical Genetic Engineering, KRL Hospital Islamabad. Methods Patients with Chronic Myeloid Leukaemia age range–18-70 years were included in this study. One group comprised responders and the other group comprised non-responders. Imatinib trough levels in both groups were determined using High-performance Liquid Chromatography and compared, and the association was determined with therapeutic outcomes. DNA was extracted, and the PCR restriction fragment length polymorphism technique was used to identify the alleles. The results were analyzed using Statistical Package for Social Sciences (SPSS) version 22.0. Results The imatinib concentration in patients with the homozygous wild allele CC of rs2242480 was higher(1298ng/ml) as compared with the mutant homozygous TT allele (489ng/ml) or heterozygous allele CT(873ng/ml) Conclusion There was a significant association between imatinib trough levels and CYP3A4 polymorphism, and trough concentration was found to be lower in patients with the TT or CT variant of rs2242480 than in patients with the CC genotype.

The Frequencies distribution of CYP3A5 rs776746 and ABCB1 rs1045642 polymorphisms in the west Algerian population and relationships with pharmacogenetics.

Pharmacogenetic markers, such as the ATP Binding Cassette (ABCB1) and cytochrome P450 (CYP) 3A5 enzymes, play a crucial role in personalized medicine by influencing drug efficacy and toxicity based on individuals' or populations' genetic variations.This study aims to investigate the genetic polymorphisms of CYP3A5 (rs776746) and ABCB1 (rs1045642) in the West Algerian population and compare the genotypes and allelic distributions with those of various ethnic groups. The study involved 472 unrelated healthy subjects from the Western Algerian population. DNA genotyping was performed using TaqMan allelic discrimination assay. The variants in our population were compared to those in other ethnic groups available in the 1000 Genomes Project. Genotype and allele frequencies were calculated using the chi-square test and the Hardy-Weinberg equilibrium (HWE). The minor allele frequencies were found to be 0.21 for CYP3A5 6986A and 0.34 for ABCB1 3435T. These frequencies were similar to those observed in North African populations, while notable differences were observed in comparison to certain Caucasian and African populations. The difference in the allelic and genotypic distribution of these polymorphisms emphasize the need for dose adjustments in drugs metabolized by CYP3A5 and transported by ABCB1 to optimize treatments outcomes.

Polymorphic Loci of Xenobiotic Biotransformation Genes in Accumulated Mercury Pollution Liquidators and in Workers with Chronic Mercury Vapors Exposure.

The allele and genotype frequencies of the polymorphic loci CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), GSTM1, and GSTT1 genes were studied in 517 men: in 389 accumulated mercury pollution liquidators (207 firefighters of the Ministry of the Russian Federation for Civil Defence, Emergencies and Elimination of Consequences of Natural Disasters and 182 employees of the Federal Environmental Operator) and 128 former workers (82 patients in the delayed period of chronic mercury intoxication and 46 individuals contacted with mercury and had no chronic mercury intoxication). We found differences in the frequencies of AA and AG genotypes in groups of former workers (χ2=6.96, p=0.008) for the polymorphic locus rs1048943, while the AG-CYP1A1 genotype was characterized by a 5.5-fold decrease in the odds ratio for the development of chronic mercury intoxication (OR=0.18, p=0.0041). An unfavorable combination of genotypes of the studied polymorphic loci increases the risk of undesirable health effects.

Very important pharmacogenetic variants landscape and potential clinical relevance in the Zhuang population from Yunnan province

The gradual evolution of pharmacogenomics has shed light on the genetic basis for inter-individual drug response variations across diverse populations. This study aimed to identify pharmacogenomic variants that differ in Zhuang population compared with other populations and investigate their potential clinical relevance in gene-drug and genotypic-phenotypic associations. A total of 48 variants from 24 genes were genotyped in 200 Zhuang subjects using the Agena MassARRAY platform. The allele frequencies and genotype distribution data of 26 populations were obtained from the 1000 Genomes Project, followed by a comparison and statistical analysis. After Bonferroni correction, significant differences in genotype frequencies were observed of CYP3A5 (rs776746), ACE (rs4291), KCNH2 (rs1805123), and CYP2D6 (rs1065852) between the Zhuang population and the other 26 populations. It was also found that the Chinese Dai in Xishuangbanna, China, Han Chinese in Beijing, China, and Southern Han Chinese, China showed least deviation from the Zhuang population. The Esan in Nigeria, Gambian in Western Division, The Gambia, and Yoruba in Ibadan, Nigeria exhibited the largest differences. This was also proved by structural analysis, Fst analysis and phylogenetic tree. Furthermore, these differential variants may be associated with the pharmacological efficacy and toxicity of Captopril, Amlodipine, Lisinopril, metoclopramide, and alpha-hydroxymetoprolol in the Zhuang population. Our study has filled the gap of pharmacogenomic information in the Zhuang population and has provided a theoretical framework for the secure administration of drugs in the Zhuang population.

Single-Nucleotide Polymorphisms Associated with Mercury Levels and Neurological Symptoms: An Overview.

Mercury (Hg) pollution is a global public health concern because of its adverse effects on the environment and health. Single-nucleotide polymorphisms (SNPs) have been associated with Hg levels and outcomes. The aim of this review was to describe the research and discuss the evidence on the genetic susceptibility of Hg-exposed individuals to the development of neurocognitive disorders. A systematic review was performed to identify the genes/SNPs associated with Hg toxicokinetics and that, therefore, affect neurological function in exposed populations. Observational and experimental studies were identified by screening three databases. Thirteen articles were included (quality score 82-100%) and 8124 individuals were evaluated. Hg exposure was mainly fish consumption (77%) and, in 31% of the studies, the Hg levels exceeded the reference limits. Genetic susceptibility to higher Hg levels and neurotoxicity risk in Hg poisoning were associated with eight (ALAD rs1800435, CYP3A4 rs2740574, CYP3A5 rs776746, CYP3A7 rs2257401, GSTP1 rs1695, MT1A rs8052394, MT1M rs2270836, and MT4 rs11643815) and three (MT1A rs8052394, MT1M rs2270837, and MT2A rs10636) SNPs, respectively, and rs8052394 was associated with both outcomes. The MT1A rs8052394 SNP may be used as a susceptibility biomarker to identify individuals at greater risk for higher Hg levels and the development of neurocognitive disorders in metal-exposed populations.