Pharmacogenomics最新文献

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.

Aim: This study aims to better understand the utility of pharmacogenomic (PGx) testing for the rare disease, Prader-Willi syndrome (PWS).

Methods: Individuals with PWS received PGx testing, and their caregivers were surveyed 1 month after receiving results (n = 42) and 6-months after receiving results (n = 38). A subset of respondents (n = 9) also participated in qualitative interviews.

Results: After receiving the PGx results, only one caregiver participant (2.27%) reported making medication changes. Eighty percent of caregiver participants stated the most valuable aspect of the PGx results was the information it provided about future medications their child may need. Interview participants discussed how the report gave them reassurance or verification of their current medication regimen. Only 36.59% of caregiver participants shared PGx results with their child's healthcare providers during the six-month follow-up period. Interview participants described reasons for not sharing the PGx report, including that nothing in the report prompted them to do so, or that they believed providers would not use it.

Conclusion: PGx results are perceived as valuable to the PWS population, but sharing PGx results with healthcare providers was limited at the six-month time point.

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.

Aim: This study aimed to evaluate the efficacy of thalidomide in transfusion-dependent β-thalassemia (TDT) patients and explore its association with CYP2C19 polymorphisms (rs12248560 and rs4244285).

Methods: Hemoglobin levels of 190 TDT patients were assessed at baseline and after 3, 6, and 12 months of thalidomide treatment. Patients were categorized into response groups based on Hb improvement. Genotyping of rs12248560 and rs4244285 was performed using Sanger sequencing.

Results: The Hb levels of study patients increased from baseline (6.6 ± 1.12 g/dL) to 12 months (8.0 ± 2.03 g/dL) of thalidomide treatment (p < 0.001). Thirty-five (36.8%) patients were excellent responders, 24 (25.3%) good, 12 (12.6%) partial, and 24 (25.3%) non-responders. The genotype patterns were as follows: 88 (46.3%) were CC, 84 (44.2%) were CT, and 18 (9.5%) were TT for rs12248560, while 74 (38.9%) were GG, 46 (45.3%) were GA, and 30 (15.8%) were AA for rs4244285. Response to thalidomide was significantly better in patients having minor allele T at rs12248560(p < 0.05).

Conclusion: The findings suggest thalidomide as an effective option for TDT and highlight the potential role of CYP2C19 genetic variation in modulating treatment response.

Aim: Pharmacogenomics enables treatments to be tailored to individual genetic profiles, optimizing efficacy while reducing adverse effects. The Clinical Pharmacogenetics Implementation Consortium (CPIC) classifies gene-drug pairs by their level of evidence. Level A and B pairs are considered actionable, indicating that prescribers should (A) or could (B) modify therapy.

Materials and methods: This cross-sectional study aimed to assess the prevalence of actionable CPIC variants in the Montreal Heart Institute (MHI) Hospital Cohort. Genotyping was performed at the MHI Beaulieu-Saucier Pharmacogenomics Center using Agena's MassARRAY and Illumina's Global Screening Array. Genes ABCG2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, DPYD, HLA-A, HLA-B, SLCO1B1, TPMT, UGT1A1, and VKORC1 were analyzed in 10,082 participants.

Results: Participants had an average of 3.9 genes with actionable variants, and among the full cohort, 99.7% carried at least one actionable variant. Of the 65 CPIC level A or B gene-drug pairs evaluated, 57 involved medications used by at least one participant. Nearly 40% of participants had at least one actionable gene-drug pair - that is, they were taking a medication for which they carried an actionable variant.

Conclusion: This study confirms the high prevalence of actionable genetic variants in individuals with or at high risk of cardiovascular diseases.

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).