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.

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.

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.

Provider attitudes on the clinical applicability of pharmacogenomics (PGx) are variable. We investigated psychiatry provider perspectives on PGx testing to gauge familiarity, implementation barriers/facilitators, and educational gaps within the Johns Hopkins Health System (JHHS). A 63-question survey was disseminated to psychiatry attending physicians and trainees practicing at JHHS. The survey queried familiarity with PGx testing, its clinical utility, barriers, benefits, the future landscape of PGx, and improvements in PGx implementation. Responses were categorized using a Likert scale and analyzed with Mann-Whitney non-parametric statistical testing. Within our health system, a minority of respondents were aware of PGx resources and there was mixed comfortability in the utilization and interpretation of PGx results. There were mixed opinions regarding the current clinical benefits of PGx testing but there was a desire for further education/training and strong agreement regarding the increased role of PGx in the future of psychiatric practice. Areas where PGx could be improved for greater clinical integration were also identified. While current PGx perspectives are mixed, there is agreement that PGx will play a greater role in psychiatry, highlighting the importance of PGx education and testing integration within a framework which promotes multi-disciplinary consultation to overcome implementation and interpretation challenges.

Aims: Deferiprone, an iron chelator, causes variable adverse drug reactions (ADRs) in β-thalassemia patients, suggesting a role for pharmacogenetic factors. To address the lack of comprehensive pharmacogenetic data, this study investigated the association between four common UGT1A6 variants - the primary enzyme metabolizing deferiprone - and the occurrence of specific ADRs, considering relevant clinical and personal characteristics.

Patients & methods: A retrospective cohort of 178 Iranian β-thalassemia major patients on deferiprone was studied. ADRs - arthralgia, gastrointestinal (GI) complications, neutropenia, and liver enzyme elevations - were defined using clinical guidelines, confirmed by medical records, and supplemented by questionnaires. Four UGT1A6 polymorphisms were genotyped, and associations were evaluated using a complication-specific framework and diplotype - haplotype analyses, adjusting for ten demographic, clinical, and treatment variables.

Results: Overall ADR incidence was not significantly associated with individual SNPs. Stratified analysis revealed that the AA - GC diplotype (rs2070959-rs1105879) was associated with reduced arthralgia risk (OR = 0.28, p = 0.022), whereas the GC - AC diplotype was linked to increased GI complication risk (OR = 5.48, p = 0.007) and showed a near-significant association with neutropenia. Female sex was associated only with increased GI complications (p = 0.002).

Conclusions: Specific UGT1A6 diplotypes and sex are differentially associated with distinct deferiprone-related ADRs. A complication-specific pharmacogenetic approach can improve understanding of deferiprone-related ADRs.

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).

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.

Background: Screening for dihydropyrimidine dehydrogenase (DPD) deficiency has been recommended by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) to prevent fluoropyrimidine toxicity. Depending on national guidelines, it relies on phenotyping or variants genotyping. We assessed the benefit of DPYD sequencing to identify unreported variants that may alter enzyme function.

Methods: We retrospectively analyzed DPYD next-generation sequencing results obtained from 1145 individuals at Limoges University Hospital between November 2020 and July 2025.

Results: Fifty-one DPYD variants were identified including several rare variants and copy-number variation (CNV) that are not addressed in current guidelines. Four were common (MAF ≥ 5%), 6 rare (MAF ≥ 0.5% and < 5%) and 41 very rare (MAF < 0.5%). Eight showed a Clinical Pharmacogenetics Implementation Consortium (CPIC) score indicative of decreased or null activity; 12 were classified normal-function allele, and 31 had no CPIC annotation. In this cohort, 73 (6.3%) individuals carried at least one decreased-function allele, while 28 (2.4%) had potentially damaging rare or structural variants (including 5 CNVs).

Conclusion: NGS analysis enables the identification of DPYD rare or structural variants with potential functional impact, thereby improving the genetic assessment of DPD deficiency.