Pharmacogenomics最新文献

Pharmacogenomic (PGx) testing can help guide medication prescribing for a wide range of health indications. The objective of this scoping review was to understand how PGx testing has been clinically implemented and learn from these experiences. Research questions guiding this work were: (1) what different models for delivery of PGx testing have been employed? (2) what are the characteristics of each delivery model? and (3) what are the reported facilitators and barriers associated with each delivery model? A total of 134 articles reported on 125 PGx initiatives spanning 19 countries. Four unique delivery models were identified: sole prescriber-led (n = 45), prescriber-led within an interdisciplinary care team (n = 34), community pharmacist-led (n = 16), and PGx consultation service (n = 30). The unique combination of characteristics, and reported facilitators and barriers yielded distinct strengths and challenges for each identified delivery model. Findings from this review can help inform future implementation planning or expansion of PGx initiatives by presenting different delivery models that may be employed and the corresponding considerations for each approach. This information can help inform future implementers in the selection of one or more approaches that may be most suitable based on their unique contextual needs, and available infrastructures or resources.

Aims: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Although PEG-asparaginase (PEG-ASNase) is a key drug in treatment, hypersensitivity reactions, pancreatitis, and silent inactivation remain major challenges. Interindividual genetic variability influences drug metabolism and toxicity, and pharmacogenetic research aims to identify these variants early to predict specific responses effectively.

Methods: We investigated the association between variants in NFATC2, GRIA1, CNOT3, MYBBP1A, ARHGAP28, ULK2, and RGS6 and PEG-ASNase - induced toxicities in a prospective multicenter study of 441 children with ALL. Genotyping was performed using TaqMan probes on saliva-extracted DNA.

Results: Among patients, 9.7% developed allergies, 3.4% pancreatitis, and 10.1% silent inactivation, which was significantly associated with allergic reactions (p < 0.05). No significant associations were found between the genetic variants and hypersensitivity or pancreatitis (p > 0.05).

Conclusions: No statistically significant associations were observed between the selected variants and PEG-ASNase-related hypersensitivity or pancreatitis in this cohort.This study highlights the importance of ancestry-informed approaches in pharmacogenomic research for ALL.

Aim: This study investigated the impact of ABCB1 gene polymorphisms on clopidogrel absorption and therapeutic response by analyzing plasma levels of the clopidogrel carboxylic acid metabolite (CAM), and cardiovascular events (CVEs) in patients undergoing percutaneous coronary intervention (PCI).

Methods: A prospective cohort study of 264 post-PCI patients was conducted in Peshawar, Pakistan. CVEs over 12 months were recorded. Plasma concentrations of CAM were measured by high-performance liquid chromatography (HPLC), while the ABCB1 gene (rs1045642) was genotyped by Sanger sequencing to determine associations between genetic variants, CAM levels, and clinical outcomes.

Results: The study documented 54 CVEs, including 13 deaths, 6 stent thromboses, 10 recurrent myocardial infarctions, 23 ischemic events requiring hospitalization, and 2 strokes. The analysis showed that 31.1% of patients had subtherapeutic CAM levels ( <2000 ng/ml), while 68.9% had therapeutic levels. Genetic analysis identified 65% as poor absorbers (CT/TT genotypes) and 35% as good absorbers (CC genotype), while CAM levels were significantly associated with the CT/TT genotype (p < 0.005).

Conclusion: This study linking ABCB1 variation to CAM concentration and therapeutic outcomes. There was a significant association between ABCB1 variants and CAM concentrations. However, no association was found between ABCB1 polymorphisms and CVEs.

Background: Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme responsible for metabolizing approximately 20% of commonly prescribed drugs. Its genetic variability contributes to interindividual and interethnic differences in drug response. However, large-scale studies on CYP2D6 allele distributions in the Korean population remain limited.

Methods: We conducted CYP2D6 genotyping, including copy number variation analysis, in 3,874 unrelated Korean individuals recruited from five university hospitals. Genotypes were assigned diplotypes and phenotypes using the CPIC activity score system.

Results: The most frequent allele was the decreased-function *10 (44.9%), followed by normal-function *1 (32.8%) and 2 (11.0%). The gene deletion five accounted for 5.7%. Among phenotypes, 62.2% were extensive metabolizers, 36.1% intermediate metabolizers, 0.9% ultrarapid metabolizers, and 0.4% poor metabolizers. We also identified CYP2D6 × 65, previously unreported in Koreans, and a novel duplication variant, CYP2D6 × 49x2.

Conclusion: This is the largest study of CYP2D6 polymorphisms in a Korean population to date. It provides a comprehensive reference for Korean pharmacogenomics and highlights important interethnic differences. The findings support the development of personalized medicine strategies based on population-specific pharmacogenetic data.

Background: Despite proven efficacy of statins in stroke prevention, genetic factors may influence individual stroke risk among statin users. With increasing precision medicine approaches and growing evidence of population-specific genetic variations, identifying genetic markers that predict stroke risk in statin-treated Asian populations has become critically important for personalized cardiovascular prevention strategies.

Methods: We conducted a genome-wide association study of 1,678 participants using lipid-lowering agents in the Korean Genome and Epidemiology Study (KoGES) cohort. Significant findings were replicated in 2,170 Asian participants on statins from the UK Biobank using an additive genetic model adjusted for relevant covariates.

Results: In the discovery analysis, 83 single nucleotide polymorphisms were suggestively associated with stroke (p <1.0 × 10^-5). Among these, 21 SNPs in the CDH13 gene were associated with increased stroke risk. The lead SNP, rs7201829, was significantly replicated in the UK Biobank (odds ratio: 2.29, p = 2.39 × 10^-5).

Conclusions: This study identified CDH13 as a significant genetic marker associated with stroke risk among Asian statin users. These findings provide the first genome-wide evidence for genetic determinants of stroke susceptibility during statin therapy, supporting the development of personalized prevention strategies in Asian populations.

Diabetes is a chronic disease that affects approximately 589 million people worldwide. Type 2 diabetes is one of its main forms (~90%) and manifests as hyperglycemia due to the resistance of myocytes and adipocytes to insulin. These are unable to capture and use blood glucose. In the long term, T2D can lead to a reduced production of insulin by beta cells, leading to more complex complications. Metformin is the first-line treatment for this condition. However, it may not always be effective for regulating blood glucose levels. Some factors, such as genetics, may influence the drug efficacy for this disease. The aim of this review is to summarize the pharmacogenetic variants associated with response to metformin in T2D treatment.

Your hospital has decided to introduce a pharmacogenomics program. What do you need to do to realize this ambition? In this paper, we set out the elements that should be considered, including the team and resources required to establish a sustainable program. This will draw on experience from successful global pharmacogenomic programs and will highlight key interdependencies, opportunities and challenges.

Background: Ensuring the efficacy and safety of medicines acting on the central nervous system (CNS) remains a challenge due to their complex pharmacokinetics and inter-individual variability in response. We describe the frequencies of pharmacogenomic variants affecting CNS drug metabolism in a Sri Lankan population.

Methods: Pharmacogenomic data pertaining to genes of interest were obtained from the Pharmacogenomics Knowledgebase database. Pharmacokinetically relevant cytochrome P450 isoforms were selected. Their frequencies in Sri Lankans were obtained from an anonymized database derived from 690 participants, from the Human Genetics Unit, Faculty of Medicine, University of Colombo. Minor allele frequencies (MAFs) of these variants were calculated and compared with other populations.

Results: MAFs of CYP2C19 rs4244285, CYP2D6 rs16947, CYP2D6 rs1058164, CYP2D6 rs1135840, and CYP2B6 rs3745274 were notably high at 40.9% (95%CI:38.3-43.5), 58.0% (95%CI:55.3-60.6), 43.8% (95%CI:41.1-46.4), 44.1% (95%CI:41.5-46.8), and 39.8% (95%CI:37.2-42.4), respectively. MAFs of CYP2C9 rs72558189, CYP2C19 rs4244285, CYP2D6 rs77913725, CYP2D6 rs1135828, and CYP2B6 rs3745274 recorded the highest in Sri Lankans when compared to all other populations. A lower prevalence was noted in MAFs of CYP2D6 rs1065852, CYP2D6 rs16947, and CYP2D6 rs28371706.

Conclusion: Sri Lankans exhibit an increased susceptibility to adverse reactions with common antidepressants, antipsychotics, and analgesics and reduced efficacy to opioid analgesics. These findings highlight the need for population-specific pharmacogenomic guidelines.

Background: Preemptive pharmacogenomic (PGx) testing is a candidate for broad implementation because of its potential to improve medication safety and outcomes. However, little is known about how patients may process preemptively generated PGx information.

Methods: We conducted a survey study in a cohort of 5,000 individuals receiving preemptive PGx testing in a primary care clinic in the USA. We assessed patients' perceived understanding of results and confidence in current prescription drugs and doses before and after they received PGx information.

Results: 4,624 individuals completed the pre-results survey (92.8% survey completion rate), and 3,408 (74.4% of pre-results survey completers) completed the post-results survey. Participants currently taking prescription medications were more likely to report inability to understand their PGx results. Additionally, participants' confidence in their current prescription drugs and drug doses declined following receipt of PGx results, and this decline was associated with number of prescriptions and perceived understanding of PGx results. Health literacy and educational attainment were not associated with reduced confidence.

Conclusion: As preemptive PGx testing is considered for implementation in primary care settings, care must be taken to support patients with preexisting prescriptions to ensure adequate understanding of the immediate relevancy and actionability of PGx results in their healthcare.

Background and aims: The SLCO gene family encodes OATP-like transporters that interact with statins and may influence their efficacy. Consequently, these genes are key targets in pharmacogenetic studies, and associations between SLCO1B1 variants and statin therapeutic response have already been demonstrated. The aim of this study was to evaluate the association between the SLCO1B1 gene polymorphisms rs2306283, rs11045819, rs4149056, and the SLCO1B3 gene polymorphism rs4149117, and the regularity of statin treatment.

Material and methods: This was a cohort study involving the review of 477 patient medical records and genotyping for the variants of interest. All patients were on simvastatin or atorvastatin therapy. Cox regression analysis was used to assess the association between genotypes and treatment regularity. Irregular treatment was defined by the occurrence of one or more of the following: 1) dose increase, 2) dose reduction, 3) treatment discontinuation, or 4) statin substitution.

Results: For rs2306283 (c.388A > G), carriers of the G allele had a significantly higher risk of treatment irregularities (Hazard Ratio: 1.50; 95% CI: 1.05-2.13; p = 0.024). For rs4149056 (c.521T > C), CC homozygotes showed a significantly increased risk of statin substitution and treatment discontinuation (Hazard Ratio: 2.16; 95% CI: 1.04-4.44; p = 0.037).

Conclusion: Our findings suggest an association between specific SLCO gene variants and irregularities in statin treatment.