Pharmacogenomics最新文献

Posttransplantation diabetes mellitus (PTDM) is a form of diabetes developed after solid organ or stem cell transplantation. This condition shares physiopathological traits with type 2 diabetes, including insulin resistance and β-cells dysfunction and its prevalence varies significantly based on the diagnostic criteria used. Immunosuppressive drugs directly contribute to PTDM risk through intricate impacts on glucose regulation, insulin secretion, and inflammation. In addition, modifiable and non-modifiable environmental risk factors are associated with the onset of this condition. This review aims to provide a comprehensive overview of the multifactorial nature of PTDM in order to highlight candidate genes and variants for pharmacogenetic research. An extensive literature search was conducted to identify studies on pharmacological and genetic factors influencing PTDM development. This review stresses the importance of understanding these interactions for improving PTDM management and underscores the need for further research to refine preventive approaches, ultimately enhancing patient outcomes post-transplantation.

Aims: The present review explores the existing evidence on pharmacogenomic tests for prediction of lithium response in the treatment of bipolar disorder. We focused our research article on reports describing findings from genome-wide association studies, polygenic risk scores, and gene expression analyses associated with lithium response.

Methods: We conducted a non-systematic review of studies from PubMed/Medline by using terms such as "pharmacogenomics," "GWAS," "gene expression," and "lithium response." Inclusion criteria focused on original research involving human subjects and assessing lithium response outcomes as well as in vitro studies. An extensive pearl-growing strategy was employed to further enlarge the scope of the piece by capitalizing on the knowledge of study authors on the subject.

Results: The observed results, albeit promising, remain preliminary in terms of clinical relevance. Machine learning combining genetic and clinical data appears associated with moderate success in predicting lithium responsiveness. Gene expression studies and genome-wide association studies have helped identify possible targets of lithium and have the potential to support target-specific drug research.

Conclusions: Pharmacogenomics may support further discoveries in precision medicine further enlarging our understanding of the underlying mechanisms of lithium for its efficacy. However, clinical applications currently appear out of reach in the near future.

Introduction: Pharmacogenetic (PGx) screening is intended to optimize drug efficacy and reduce adverse drug reactions. Current screening options include genotyping assays for preselected PGx variants and broader next-generation sequencing panels (NGS). Few studies have directly compared preemptive PGx screening methods.

Materials and methods: The two PGx methods were compared in a cross-sectional study of adult Military Health System (MHS) clinic beneficiaries. Participants had initial targeted CYP2C19/CYP2D6 genotyping at a Military Health System Laboratory. Genotyping was followed by multi-gene NGS testing. Current prescriptions were recorded and potential drug-drug interactions screened to evaluate prescribing risk.

Results: All participants (100%) had at least one clinically actionable NGS panel result compared to 81% with targeted CYP2C19/CYP2D6 genotyping. Participants (n = 162) had an average of 6.6 (range 0-22) prescriptions and 2.7 (range 0-24) drug-drug interactions. Among those with at least one clinically actionable NGS result, 42% were currently taking medication with actionable CPIC guidelines (Level A/B), compared with 24% with CYP2C19/CYP2D6 genotyping. Sixteen participants (10%) had uncertain NGS panel results, with none for CYP2C19/CYP2D6 genotyping.

Conclusions: Preemptive multi-gene NGS detected more clinically actionable PGx results than targeted CYP2C19/CYP2D6 genotyping. Effective PGx screening in the MHS may decrease preventable adverse effects and improve military readiness.

Aim: To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites.

Methods: Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM).

Results: Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found.

Conclusion: Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.

Aim: This study is designed to address the connection between antidepressant and antipsychotic-induced hepatotoxicity with pharmacogenetic and epigenetic indicators, using a novel combined approach of CYP450 polymorphism determination and early liver injury detection via microRNA testing.

Methods: The multi-centric retrospective case-control study in Slovakia involves 151 cases with signs of hepatotoxicity and 604 controls without. Participants will be tested for selected CYP450, UGT1A1 polymorphisms, and microRNAs.

Results: Anticipated findings will test if patients with specific CYP450 and UGT1A1 polymorphisms are at higher risk for drug-induced hepatotoxicity and if plasma microRNAs hsa-miR-122-5p and hsa-miR-192-5p, alone or combined, can differentiate patients with abnormal liver function.

Conclusion: The findings could contribute to personalized treatment approach by combining genetic and epigenetic biomarkers.

Background: Macrolides are widely used antibiotics, but adverse drug reactions (ADRs), particularly in genetically predisposed individuals, can compromise their safety. This study examines the impact of pharmacogenetic markers on macrolide safety in participants with bacterial complications of influenza.

Objective: To evaluate how polymorphisms in genes encoding transporter proteins (ABCB1) and enzymes (CYP3A4, CYP3A5) influence ADR risk during macrolide therapy.

Methods: A prospective study included 100 participants with lower respiratory tract bacterial complications of influenza treated with azithromycin or erythromycin for five days. Genotyping targeted ABCB1 (3435C>T), CYP3A4 (C>T intron 6), and CYP3A5 (6986A>G) polymorphisms. ADRs were monitored daily and correlated with genetic markers.

Results: The ABCB1 (3435C>T) polymorphism was associated with higher rates of abdominal pain and diarrhea in CT and TT genotypes (OR = 2.12, p = 0.043). The CYP3A4 (C>T intron 6) polymorphism increased ADR risk in erythromycin-treated participants (OR = 24.0, p = 0.0339). No significant effects were observed for CYP3A5 (6986A>G).

Conclusion: Genetic polymorphisms in ABCB1 and CYP3A4 genes predict macrolide-related ADRs. Pharmacogenetic screening could improve macrolide safety, particularly for genetically susceptible individuals.

Aims: To ascertain and describe pharmacogenomic concepts included in the intended curriculum of accredited Australian medical schools.

Methods: Content analysis of curriculum learning objectives of Australian medical schools was conducted, focusing on keywords and phrases pertaining to pharmacogenomic education. Learning objectives related to pharmacogenomics were categorized using (1) undergraduate medical genomic competencies per the Association of Professors in Human and Medical Genetics (2) Bloom's Taxonomy for cognitive and knowledge dimensions and (3) knowledge translation (enabling science, translation science and clinical implementation).

Results: The curricula of 19 accredited medical schools in Australia were analyzed. Two-thirds (68%) contained genomic/pharmacogenomic education. Eight schools had content relating to undergraduate medical genomic competencies. Of those which had pharmacogenomic-related learning objectives, the majority (65%) were categorized in Bloom's Taxonomy's lower levels (Remember and Understand) and 15% were deemed to be at the level of 'Clinical Implementation.'

Conclusion: The majority of Australian medical schools have incorporated pharmacogenomics in their current curriculum; however, learning objectives addressing application and clinical implementation are required. Doctors have a unique role to play in implementing pharmacogenomics into clinical practice. Comprehensiveness of course curricula across all learning domains would support uptake of pharmacogenomics into routine practice.

Aims: Clopidogrel exhibits substantial variability in therapeutic response, largely contributed by genetic factors. The pharmacogenomic variants data on clopidogrel metabolism in South Asians have been sparsely studied. This study explores the impact of CYP2C19 and CES1 gene variants on clopidogrel metabolism in Sri Lankans, revealing significant pharmacogenomic insights with broader implications for South Asians.

Materials & methods: Genotype data were filtered out from an anonymized database of 690 Sri Lankans, and minor allele frequencies (MAFs) were calculated. Five variants of CYP2C19 and one variant of CES1 gene were studied.

Results: Among the five CYP2C19 variants studied, rs12769205 (A>G) and rs4244285 (G>A) had the highest MAF of 42.1% and 42.0%, respectively. The CES1 variant rs71647871 (C>T) showed a MAF of 0.2%. Sri Lankans exhibited significantly higher MAFs for key variants compared to populations such as Europeans, African Americans, and East Asians (p < 0.05).

Conclusion: Given that South Asians share genetic similarities, these findings suggest that a substantial proportion of the region's population may also be poor responders to clopidogrel, increasing the risk of adverse outcomes. This highlights the importance of genotype-guided antiplatelet therapy, which could improve clinical outcomes across South Asia amidst rising cardiovascular disease rates.

Aim: To explore the effect of CYP2D6*10 (100C > T) and ADRB1 1165 G > C polymorphisms on heart rate of post-PCI (percutaneous coronary intervention) patients treated with metoprolol succinate sustained-release tablets. Methods: A total of 756 inpatients with metoprolol succinate sustained-release tablets were selected and the genotypes of CYP2D6*10 and ADRB1 1165G > C were detected in 319 patients using gene chip detection. The target heart rate was defined as a resting heart rate < 70 beats/min. Clinical data were collected. Results: A total of 319 inpatients were enrolled in the study. The mutant allele frequencies of CYP2D6 and ADRB1 were 57.21 and 69.44%, respectively. Whatever the dose of metoprolol, the heart rates were lower in patients with homozygous mutation of CYP2D6 than those with heterozygous mutation and wild-type (p < 0.05). Nevertheless, this effect was not seen between different genotypes of ADRB1. Logistic regression analysis showed that the dose of metoprolol and the genotypes of CYP2D6 were predictors of heart rate <70 beats/min in these patients. Further multivariate analysis indicated that patients with homozygous mutation had better control of heart rates compared with those with wild-type and heterozygous mutation of CYP2D6*10 genotypes (all: p < 0.001). Conclusion:CYP2D6*10 polymorphisms were associated with the heart rate of post-PCI patients treated with metoprolol succinate sustained-release tablets.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.