Pharmacogenetics and genomics最新文献

Objectives: Genetic polymorphisms in FPGS , MTHFR , and ATIC have emerged as important modulators of methotrexate (MTX) metabolism and toxicity. We investigated the distribution of FPGS rs10106, MTHFR rs1801131, and ATIC rs2372536 polymorphisms in children with acute lymphoblastic leukemia (ALL) and assessed their influence on MTX concentrations, toxicity profiles, and clinical outcomes.

Methods: Genotyping of FPGS rs10106 G > A, MTHFR rs1801131 A > C, and ATIC rs2372536 C > G polymorphisms was conducted using the Sequenom MassARRAY iPLEX platform in 145 pediatric ALL patients.

Results: Significant ethnic differences were observed in the allelic and genotypic distributions of the three single nucleotide polymorphisms (SNPs) investigated. None of these three SNPs had a significant effect on MTX levels or toxicities. The frequencies of the ATIC rs2372536 CC genotype and C allele in ALL patients (44.8% and 68.6%, respectively) were significantly lower than those in Han Chinese in Beijing, China (58.3% and 78.2%, respectively; P  = 0.036 and 0.019, respectively). Patients carrying the ATIC rs2372536 GG genotype (36.4%, 4/11) had a significantly higher relapse rate than the CC genotype carriers (6.2%, 4/65, P  = 0.013). There, however, were no significant effects on relapse-free survival in Kaplan-Meier and Cox regression analyses for all three candidate SNPs.

Conclusion: Our findings offer valuable insights into the intricate interplay between genetic polymorphisms, MTX exposure, toxicities, and clinical outcomes in patients with ALL and have the potential to inform precision medicine strategies.

In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (C trough ). Here, we characterize the impact on dolutegravir C trough of UGT1A1 , AADAC , and NAT2 polymorphisms that affect dolutegravir, rifapentine, and isoniazid, respectively. People with HIV receiving dolutegravir-based antiretroviral therapy with an indication to treat latent tuberculosis underwent pharmacokinetic sampling during dolutegravir 50 mg once daily alone, and on day 28 of dolutegravir 50 mg twice daily with rifapentine/isoniazid. Multivariable linear regression models characterized genetic associations with dolutegravir C trough . Among 30 participants evaluable for genetic associations, median (Q1, Q3) day 0 dolutegravir C trough was 1745 (1099, 2694) ng/ml, and day 28 was 2146 (1412, 2484) ng/ml. Day 28 C trough was higher with UGT1A1 rs887829 TT [geometric mean ratio (GMR) = 1.65; 90% confidence interval (CI): 0.97-2.78] and CT (GMR = 1.38; 90% CI: 1.02-1.86) than with CC, and was higher with AADAC rs1803155 GG (GMR = 1.79; 90% CI: 1.09-2.93) and AG (GMR = 1.48; 90% CI: 1.14-1.90) than with AA. Median day 28 C trough ranged from 1205 (1063, 1897) ng/ml with 4 total UGT1A1 and AADAC risk alleles, to 3882 and 3717 ng/ml with only one risk allele. Individuals with concomitant AADAC slow metabolizer and UGT1A1 normal metabolizer genotypes may be at greater risk for clinically significant drug-drug interactions between rifapentine/isoniazid and dolutegravir.

Objective: Heterocyclic amines (HCAs) are mutagens and carcinogens primarily generated when cooking meat at high temperatures or until well-done, and their major metabolic pathway includes hepatic N -hydroxylation via CYP1A2 followed by O -acetylation via N -acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans resulting in rapid and slow acetylators. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes.

Methods: We assessed the effect of some of the most common HCAs found in cooked meat, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, on insulin signaling and gluconeogenic gene expression in cryopreserved human hepatocytes characterized by their NAT2 genotype and phenotype to investigate the role of NAT2 genetic polymorphism in HCA-induced metabolic dysregulation.

Results: HCA treatment significantly reduced insulin-induced protein kinase B phosphorylation and significantly increased expression of genes involved in gluconeogenesis ( G6PC , PCK1 , FOXO1 , and PPARA ) in cryopreserved human hepatocytes from rapid but not from slow acetylators.

Conclusion: The findings suggest that NAT2 genetic polymorphism modifies HCA-induced insulin resistance and gluconeogenic gene expression, implying that individuals with rapid acetylator phenotype may be at greater risk of dysregulated glucose homeostasis following exposure to HCAs.

This short communication serves as an update to previously published pilot study results on bronchodilator response (BDR) in children with asthma. We expanded our cohort from 54 to 165 pediatric patients seeking emergency department care for an asthma exacerbation. We obtained measured BDR before and after albuterol administration using the Pediatric Asthma Severity Score and collected genomic DNA. Based on a literature review, we analyzed whether 21 candidate single-nucleotide polymorphisms (SNPs) were associated with BDR. Among the three SNPs initially reported in our pilot study as significantly associated with BDR (rs912142, rs7081864, and rs7903366), we confirmed that rs7081864 was still significantly associated with suboptimal BDR (odds ratio, 0.47; confidence interval, 0.24-0.92). If externally validated in broader studies, simple outpatient testing for that SNP variant could help guide pharmacologic therapy for acute asthma symptoms.

Based on driver mutations and gene expression profiles, the International Consensus Classification currently divided the entity 'Philadelphia chromosome-positive (Ph + ) B-cell precursor acute lymphoblastic leukemia (ALL)' into two subtypes: lymphoid-only and multilineage involvement (Ph + ALL-L and -M, respectively). The similar biological characteristics of Ph-like ALL and Ph + ALL drove us to assume that Ph-like ALL-M subtypes exist. This report presents two pediatric ALL cases (one Ph + and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19 + cells as well as in non-CD19 + cells, suggesting the presence of a Ph + or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.

Ibrutinib treatment is often complicated by cardiovascular side effects (CVSEs). The objective of this retrospective pharmacogenetic study is to replicate a previously reported association of 'high-risk' patients, who are homozygous carriers of at least two of GATA4 rs804280 AA, KCNQ1 rs163182 GG, and KCNQ1 rs2237895 AA, with increased risk of hypertension or atrial fibrillation, and explore associations for other pharmacogenes (e.g. CYP3A4 , CYP3A5 , CYP2D6 , and ABCB1 ) with ibrutinib CVSEs. Univariate associations with P  < 0.05 were adjusted for significant pretreatment cardiovascular conditions. In total 57 patients were included in the analysis. In the primary analysis, 'high-risk' patients were not more likely to experience hypertension or atrial fibrillation (70 vs. 41%, chi-square P value = 0.06). In secondary analyses, 'high-risk' patients were more likely to experience any CVSE during treatment (75 vs. 41%, P  = 0.013), develop a cardiac rhythm or function disorder (65 vs. 24%, P  = 0.008), and have a treatment modification due to CVSE (45 vs. 8%, P  = 0.004). Additionally, high-risk homozygous variant genotypes of KCNQ1 rs163182 GG and rs2237895 AA were each associated with an increased likelihood of treatment modifications due to CVSE (40 vs. 11%, P  = 0.021 and 45 vs. 9%, P  = 0.004, respectively) and cardiac rhythm or function disorders (60 vs. 27%, P  = 0.037 and 60 vs. 27%, P  = 0.037). This study found supportive evidence that 'high-risk' genotype was associated with increased ibrutinib CVSEs. Validation of these associations is necessary before prospective trials testing whether personalized ibrutinib treatment approaches improve clinical outcomes.

Objective: The incidence of lung adenocarcinoma (LAD) is increasing worldwide. Single-nucleotide polymorphisms in aldehyde dehydrogenase 2 family member gene ( ALDH2 ) rs671 and alcohol dehydrogenase 1B ( ADH1B ) rs1229984 are common and functionally important genetic variants to metabolize endogenous and exogenous aldehyde chemicals, related to cancer.

Methods: This is a case-control study. A total of 150 newly diagnosed LAD patients were from Kaohsiung Medical University Hospital, Taiwan, between 2019 and 2022. Two control groups, TWB-1 ( n  = 600) and TWB-2 ( n  = 29 683), were selected from Taiwan Biobank (TWB), and the case patients were frequency-matched with TWB-1 based on age category (30-60 or >60 years old), sex, and education levels. Logistic regression models were employed to analyze the association between two genetic variants and LAD risk.

Results: A significant association was noted between ALDH2 and LAD risk. Those with ALDH2 rs671 *2/*2 in TWB-1 and TWB-2 controls had a 2.68-fold (95% CI = 1.43-4.99) and a 1.83-fold (95% CI = 1.07-3.11) increased risk of LAD, respectively, compared with those with ALDH2 rs671 *1/*1 or *1/*2 , after adjusting for covariates. This association was particularly pronounced in females. No overall significant association between ADH1B rs1229984 and LAD risk was observed.

Conclusion: The findings indicate a strong and robust risk association between ALDH2 rs671*2/*2 and LAD in the Taiwan population, particularly in Taiwanese female adults.

Background: Pharmacogenomic testing can optimize drug efficacy and minimize adverse effects. CYP3A5 polymorphisms affect the metabolism of tacrolimus. We sought to estimate the budget impact of preemptive pharmacogenomic testing for CYP3A5 in pediatric heart transplantation patients from an institutional perspective.

Methods: A decision tree was constructed to estimate the budget impact of pediatric heart transplant patients (age ≤18 years) initiated on tacrolimus with and without CYP3A5 pharmacogenomic testing. The budget impact of preemptive pharmacogenomic testing versus no pharmacogenomic testing was calculated. One-way sensitivity analysis and alternative analyses were conducted to assess the robustness of results to changes in model parameters.

Results: CYP3A5 genotype-guided dosing provided savings of up to $17 225 per patient compared to standard dosing. These savings decreased to $11 759 when using another institution's data for the standard-dosing group. The time to achieve therapeutic concentration in the poor metabolizer genotype-guided dosing group had the largest impact on cost savings while the cost of the pharmacogenetic test had the smallest impact on cost savings.

Conclusion: Implementing CYP3A5 testing could save $17 225 per pediatric heart transplant patient receiving tacrolimus. As pharmacogenomic testing becomes more widespread, institutions should track resource requirements and outcomes to determine the best implementation policies going forward.

Objectives: We aimed to classify genetic variants in RYR1 and CACNA1S associated with malignant hyperthermia using biobank genotyping data in patients exposed to triggering anesthetics without malignant hyperthermia phenotype.

Methods: We identified individuals who underwent surgery and were exposed to triggering anesthetics without malignant hyperthermia phenotype and who had RYR1 or CACNA1S genotyping data available in our biobank. We classified all variants in the cohort using a Bayesian framework of the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists guidelines for variant classification and updated the posterior probabilities from this model with the new information from our biobank cohort.

Results: We identified 253 patients with 95 RYR1 variants and 12 CACNA1S variants. After applying a Bayesian framework, we classified 17 variants as benign (B), 31 as likely benign (LB), 57 as uncertain (VUS), and 2 as likely pathogenic (LP). When we incorporated evidence about unique exposures to malignant hyperthermia triggering anesthetic agents, 48 of 107 (45%) variants were downgraded (9 to B, 37 to LB, and 2 to VUS). Notably, 41 (72%) of 57 VUSs were downgraded to B or LB. When repeat anesthetics in the same individual were counted as one exposure, 42 of 107 (39%) of variants were downgraded (5 to B, 35 to LB, and 2 to VUS). Specifically, 37 (65%) of 57 VUSs were downgraded to LB.

Conclusion: Deidentified biorepositories linked with anesthetic data offer a new method of integrating clinical evidence into the assessment of variant probability of pathogenicity.

Background: Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase ( TPMT ) and nudix hydrolase 15 ( NUDT15 ) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective.

Methods: A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results.

Results: Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model.

Conclusion: Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.