Pharmacogenomics最新文献

Background: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the significant adverse effects of first-line tuberculosis therapy, frequently resulting in treatment discontinuation. Genetic polymorphisms in N-acetyltransferase 2 (NAT2), a key enzyme in the metabolism of isoniazid (an anti-TB drug), are suggested to influence AT-DILI susceptibility.

Methods: A meta-analysis of published studies was conducted to evaluate the association between NAT2 polymorphisms and the risk of AT-DILI. Literature searches were conducted in PubMed, Web of Science, Wiley, ScienceDirect, and Medline up to December 2024. A total of 48 studies comprising 11,035 patients were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Subgroup analyses were conducted based on region, study design, genotyping method, hepatotoxicity definitions, and NAT2 genetic variants. Heterogeneity, publication bias, quality assessment, and sensitivity analysis were assessed using the I² statistic, Egger's test, the Newcastle-Ottawa Scale (NOS), and the leave-one-out method, respectively.

Results: Slow acetylator genotypes were significantly associated with an increased risk of AT-DILI (pooled OR = 3.02; 95% CI = 2.50-3.64; p < 0.001). Moderate heterogeneity was observed (I² = 58.74%). No significant publication bias was observed (p = 0.199).

Conclusion: NAT2 acetylator status was significantly associated with the likelihood of experiencing hepatotoxicity related to anti-tuberculosis drugs.

Aim: To determine Penn Medicine patients' and gynecologic providers' knowledge and attitudes about pharmacogenetic (PGx) testing.

Methods: In this cross-sectional study, surveys were distributed to patients and gynecologic surgeons who participated in a randomized, prospective, open-label pilot study using PGx results to assist in the selection of postoperative analgesic medications. The primary objective was to understand patient- and provider-level factors that impact PGx test adoption.

Results: A majority (67%) of patients planned to share their results with their healthcare providers, and many patients (52%) were interested in having a PGx specialist further explain their results. Few (12%) gynecologic surgeons were confident in their ability to use PGx results to guide medication prescribing. The most common barrier identified was lack of training or experience with PGx testing (91%).

Conclusion: Patients want to share their results with their providers and desire further explanation. However, gynecologic surgeons do not feel prepared to utilize these PGx results to make prescribing decisions. Therefore, efforts focused on PGx education for physicians are essential prior to implementing testing into clinical practice.

Genetic ancestry refers to an individual's biogeographical origins inferred from correlated allele frequencies shared with individuals from similar ancestral regions. Understanding the complexities of genetic ancestry has proven beneficial in the field of pharmacogenomics (PGx), where personalized medication regimens are optimizing therapeutic outcomes while minimizing the risk of side effects. With the rise in the availability of electronic health records (EHR), population-specific genetic data can be integrated with clinical data using machine learning approaches to improve personalized treatment plans. Furthermore, multiomics data such as the transcriptome, methylome, proteome, and metabolome, paired with advances in machine learning methods, provide a more comprehensive approach to understanding genetic variation. The expansion of PGx studies in diverse populations can broaden the impact of precision medicine, particularly among underrepresented groups.

Naltrexone is an opioid receptor antagonist used to treat alcohol use disorder; however, like other commonly used addiction treatment options, it demonstrates inconsistency in treatment response. Pharmacogenomics may be used to individualize addiction treatment and identify patients who would be better candidates for this drug. Recently, the Clinical Pharmacogenomics Implementation Consortium (CPIC) provided guidelines on pharmacogenomic testing for naltrexone. Pharmacogenomic testing targets for naltrexone include pharmacodynamic genes, like the mu-opioid receptor gene OPRM1, as well as pharmacokinetic genes, like alcohol and aldehyde dehydrogenase (ADH and ALDH, respectively). In this article, we review the studies investigating the genotypes associated with either substance craving, intoxication effect, or relapse in patients receiving naltrexone to treat alcohol addiction. A common single nucleotide polymorphism (SNP) in OPRM1 called rs1799971 has been found to contribute to an improved naltrexone response in some studies. However, prospective genotype-stratified trials and meta-analyses have failed to confirm a clinically significant moderating effect. While not as studied as OPRM1, alcohol metabolizing enzymes, ALDH2 and ADH1B, may also contribute to naltrexone response. Current evidence does not support clinical implementation of genotyping for naltrexone prescribing decisions; however, further research on the pharmacogenomics of naltrexone is warranted.

Oral esketamine is a promising new therapy for treatment-resistant depression. However, concerns exist about interindividual pharmacokinetic variability. Genetic polymorphisms regulating the expression of ATP-binding cassette (ABC) transporters might influence bioavailability. Utilizing blood samples from a placebo-controlled trial investigating repeated, low dose oral esketamine (N = 18), we performed ABCB1 3435C > T and ABCG2 421C > A genotyping and measured the plasma levels of esketamine and its metabolites 4 h after dosing. For ABCB1 3435C > T, esketamine concentrations for C/C (Mdn = 3.8 µg/L), C/T (Mdn = 2.7 µg/L), and T/T (Mdn = 1.0 µg/L) were not significantly different (χ²(2) = 3.41, p = 0.182). For ABCG2 421C > A, esketamine concentrations did not differ significantly between C/A (Mdn = 1.5 µg/L) and C/C (Mdn = 2.4 µg/L) (U = 10.00, p = 0.471). Metabolite plasma concentrations were also not associated with polymorphism status. These results suggest that oral esketamine pharmacokinetics are unaffected by ABC transporter polymorphisms. However, due to the limited sample size and genotype variant representation, results are preliminary. Larger, more adequately powered studies are needed to clarify genotype effects and inform individualized esketamine therapyClinical trial registration: NTR6161 (Dutch Trial Register).

Introduction: The cytochrome P450 2C19 (CYP2C19) enzyme plays a critical role in the metabolism of several clinically important drugs, but the genetic polymorphisms of CYP2C19 have been partially characterized in the Chinese population.

Methods: Genomic DNA from 1210 Chinese Han individuals was subjected to next-generation sequencing to screen for CYP2C19 variants, and newly identified mutations were confirmed by Sanger sequencing. CYP2C19 microsomes were expressed in vitro using an insect cell expression system, and their metabolic activity toward (S)-mephenytoin was quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Results: Genetic screening of CYP2C19 gene in 1210 Chinese Han individuals was performed and identified 11 previously unreported variants. Recombinant expression of these novel variants in insect microsomes demonstrated that approximately half of the variants exhibited protein expression levels comparable to the wild type. Using (S)-mephenytoin as a probe substrate, in vitro metabolic activity assays revealed that five variants (G79X, D188fs, A297D, A297V, and T302R) exhibited abolished enzymatic activity, whereas the remaining variants showed significantly reduced activity compared to the wild-type enzyme.

Conclusion: This study reveals a high prevalence of functionally impaired rare CYP2C19 variants in the Chinese Han population, underscoring their potential clinical relevance for personalized medicine.

Aims: Sequential Anthracycline-Taxane chemotherapy is standard treatment for BC. This study examines the combined impact of low BMI and CYP polymorphisms on treatment response.

Method: BMI was assessed before chemotherapy, and clinical response was evaluated using RECIST v.1. Four SNPs in CYP2C9, CYP2C19, and CYP3A4 gene were analyzed in 148 samples using PCR-RFLP.

Results: CYP2C19 (G681A) was significantly associated with treatment non-responsiveness in all genetic models namely dominant (OR11.119; 95%CI [5.103-24.228], p < 0.0001), recessive (15.818; [4.548-55.015]; p < 0.0001), codominant (χ² 48.229; p < 0.0001). No significant association was found in other two genes CYP2C9 (C430T, A32621C) and CYP3A4 (A392G). When combined with BMI, the CYP2C19 AA genotype showed significant associations with poor treatment response for low BMI group across all genetic models: dominant (9.60; [2.892-31.864]; p < 0.0001), recessive (1.473; [1.404-2.164]; p < 0.001), and codominant (χ² 18.897; p < 0.0001) and AA associated with lowest PFS: 38 months; HR >1. OS (39.79 months; p = 0.039) were lowered among GA genotype with increased HR (HR 3.78; p = 0.031).

Conclusion: AA genotype at G681A in low BMI patients showed the poorest chemotherapy response and lowest PFS (HR>1). CYP2C19 variants (AA) may serve as predictive markers for non-responsiveness towards AC-T chemotherapy in low BMI BC patients, highlighting the need for genetic counselling and nutritional support to improve treatment outcomes.

Introduction: Precision medicine is the future of healthcare, and pharmacists are well-positioned to play a key role in pharmacogenomics (PGx). Experiential learning offers valuable opportunities to gain hands-on experience in clinical PGx practices. This study aimed to explore experiential learning opportunities in PGx for pharmacy education.

Methods: Four PGx clinics in the United States of America, which provide PGx services, were observed to assess the potential for experiential learning. Qualitative data were collected through observations of PGx clinic consultations and semi-structured interviews with four pharmacists, one at each site. This approach provided insight into the practice-based learning opportunities in PGx clinics to explore experiential learning.

Results: Multiple experiential learning opportunities were identified, including activities to develop knowledge and skills; conduct research; collaborate with an interprofessional team; create patient education resources; provide patient and healthcare education; provide comprehensive care; develop evidence-based medicine skills, including the use of PGx resources; address ethical, legal, and social implications of PGx, and leadership.

Conclusion: Pharmacogenomics clinics offer valuable experiential learning opportunities for pharmacy education. Collaboration between healthcare and higher education institutions is essential to create these opportunities, ensuring the development of pharmacists who are prepared to meet future healthcare needs.

Introduction: Transient ischemic attack (TIA) or ischemic stroke (IS) patients may have recurrent stroke incidents, especially when carrying CYP2C19 Loss-of-Function (LoF) alleles and taking clopidogrel. Recent studies suggest using alternative antiplatelets, e.g., prasugrel, ticagrelor, in these patients. However, the aggregated risk of recurrent stroke or composite vascular events in CYP2C19 genotype-guided prasugrel/ticagrelor against clopidogrel therapy in such TIA/IS patients remained unexplored.

Methods: A database search was performed to retrieve relevant studies. RevMan software was used to calculate the risk ratio (RR), considering p < 0.05 statistically significant.

Result: Six studies (14,124 TIA/IS patients) were considered. TIA/IS patients carrying CYP2C19 LoF alleles on ticagrelor/prasugrel therapy were associated with a significant reduction in the risk of composite vascular events (RR 0.76, 95% CI 0.66-0.89; p = 0.0004) and recurrent stroke (RR 0.76, 95% CI 0.64-0.90; p = 0.002) compared to the clopidogrel therapy. However, the bleeding events did not differ significantly (RR 0.91, 95% CI 0.65-1.27; p = 0.58) between the treatment groups.

Conclusion: TIA/IS patients inheriting CYP2C19 LoF alleles taking ticagrelor/prasugrel may significantly optimize the overall clinical benefits compared to those who are taking clopidogrel by reducing composite vascular events and recurrent stroke without elevating the risk of bleeding events.