Pharmacogenetics and genomics最新文献

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.

Background: Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.

Methods: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.

Results: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A , and the genes METTL17 and PRSS57 , but none achieved genome-wide significance.

Conclusion: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence.

Objective: Drug-induced long QT syndrome (diLQTS) is an adverse reaction from over 150 FDA-approved medications, posing the risk of triggering torsades de pointes and sudden death. While common genetic variants may modestly impact QT interval individually, their collective effect can significantly amplify risk of diLQTS. Consequently, this study aimed to validate a polygenic risk score (PRS) for diLQTS previously proposed by Strauss et al .

Methods: A retrospective cohort study was conducted utilizing patients from the Michigan Genomics Initiative prescribed 27 high-risk QT-prolonging drugs and an ECG during the prescription. The primary outcome was marked prolongation of the QTc interval (either >60 ms change from baseline or >500 ms absolute value) during treatment with a high-risk QT-prolonging drug.

Results: The primary outcome occurred in 12.0% of n  = 6070 self-reported White, 12.4% of 558 African American, and 8.2% of 110 Asian patients. The PRS significantly associated with diLQTS in White patients [adjusted odds ratio = 1.44 (95% CI: 1.09-1.89); P  = 0.009]. However the study lacked sufficient statistical power to confirm the PRS as a risk factor in African Americans [adjusted odds ratio = 2.18 (95% CI: 0.98-5.49); P  = 0.073] and Asians [adjusted odds ratio = 3.21 (95% CI: 0.69-16.87); P  = 0.139] due to smaller sample sizes in these groups.

Conclusion: The previously published PRS for diLQTS was validated in a large, real-world cohort, demonstrating its potential as a tool for identifying high-risk patients. Incorporating this PRS into routine clinical practice could enable proactive measures to prevent life-threatening diLQTS.

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.

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.

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.

Objectives: We report, for the first time, the distribution of four no-function NAT2 single nucleotide polymorphisms and inferred NAT2 acetylator phenotypes in three indigenous groups (Munduruku, Paiter-Suruí, and Yanomami), living in reservation areas in the Brazilian Amazon.

Methods: Two hundred and seventy-six participants from three indigenous groups (92 for each group) were included and genotyped for four NAT2 polymorphisms (rs1801279, rs1801280, rs1799930, and rs1799931) by the TaqMan system. Minor Allele Frequency (MAF) was determined and NAT2 acetylator phenotypes were inferred.

Results: NAT2 rs1801279G>A was absent in all cohorts; rs1799930G>A was absent in Yanomami and rare (MAF 0.016) in Munduruku and Paiter-Suruí; MAF of rs1801280T>C ranged five-fold (0.092-0.433), and MAF of rs1799931G>A varied between 0.179 and 0.283, among the three groups. The distribution of NAT2 phenotypes differed significantly across cohorts; the prevalence of the slow acetylator phenotype ranged from 16.3% in Yanomami to 33.3% in Munduruku to 48.9% in Paiter-Suruí. This three-fold range of variation is of major clinical relevance because the NAT2 slow phenotype is associated with higher risk of hepatotoxicity with antituberculosis chemotherapy and high incidence rates of tuberculosis and burden of latent infection among Munduruku, Paiter-Surui, and Yanomami peoples. According to the frequency of the NAT2 slow acetylator phenotype, the estimated number of individuals needed to be genotyped to prevent one additional event of hepatotoxicity range from 31 (Munduruku) to 39 (Paiter-Surui) and to 67 (Yanomami).

Conclusion: The rs1801279 polymorphism was not found in any of the cohorts, while the MAF of the other polymorphisms showed significant variation between the cohorts. The difference in the prevalence of the NAT2 slow acetylator phenotype, which is linked to isoniazid-induced hepatotoxicity, was observed in the different study cohorts.