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Farmacia Hospitalaria : Organo Oficial... Feb 2024Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is... (Review)
Review
INTRODUCTION
Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine.
MATERIALS AND METHODS
A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualizing dosing", "clinical routine", and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis.
RESULTS
49 articles were included for the final analysis following review by 2 investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNFα agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found.
CONCLUSION
The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.
PubMed: 38341366
DOI: 10.1016/j.farma.2023.12.004 -
Frontiers in Pharmacology 2023
PubMed: 38026952
DOI: 10.3389/fphar.2023.1307602 -
CMAJ : Canadian Medical Association... Nov 2023Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of...
BACKGROUND
Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants.
METHODS
We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC.
RESULTS
Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation.
INTERPRETATION
Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.
Topics: Adult; Humans; Depressive Disorder, Major; Pharmacogenetics; Depression; Cost-Benefit Analysis; Antidepressive Agents; Quality-Adjusted Life Years; British Columbia
PubMed: 37963621
DOI: 10.1503/cmaj.221785 -
Schizophrenia Research May 2024Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of... (Review)
Review
Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.
Topics: Humans; Schizophrenia; Pharmacogenetics; Genetic Testing; Genetic Counseling; Multifactorial Inheritance; Genetic Predisposition to Disease
PubMed: 37813777
DOI: 10.1016/j.schres.2023.09.042 -
Frontiers in Oncology 2023Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data...
BACKGROUND
Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data have the potential to be repurposed to support clinical pharmacogenomics (PGx), current computational approaches have not been widely validated using clinical data. In this study, we assessed the accuracy of the Aldy computational method to extract PGx genotypes from WGS and WES data for 14 and 13 major pharmacogenes, respectively.
METHODS
Germline DNA was isolated from whole blood samples collected for 264 patients seen at our institutional molecular solid tumor board. DNA was used for panel-based genotyping within our institutional Clinical Laboratory Improvement Amendments- (CLIA-) certified PGx laboratory. DNA was also sent to other CLIA-certified commercial laboratories for clinical WGS or WES. Aldy v3.3 and v4.4 were used to extract PGx genotypes from these NGS data, and results were compared to the panel-based genotyping reference standard that contained 45 star allele-defining variants within , , , , , , , , , , , , , and .
RESULTS
Mean WGS read depth was >30x for all variant regions except for (average read depth was 29 reads), and mean WES read depth was >30x for all variant regions. For 94 patients with WGS, Aldy v3.3 diplotype calls were concordant with those from the genotyping reference standard in 99.5% of cases when excluding diplotypes with additional major star alleles not tested by targeted genotyping, ambiguous phasing, and hybrid alleles. Aldy v3.3 identified 15 additional clinically actionable star alleles not covered by genotyping within , , , , and . Within the WGS cohort, Aldy v4.4 diplotype calls were concordant with those from genotyping in 99.7% of cases. When excluding patients with copy number variation, all Aldy v4.4 diplotype calls except for one diplotype call were concordant with genotyping for 161 patients in the WES cohort.
CONCLUSION
Aldy v3.3 and v4.4 called diplotypes for major pharmacogenes from clinical WES and WGS data with >99% accuracy. These findings support the use of Aldy to repurpose clinical NGS data to inform clinical PGx.
PubMed: 37469403
DOI: 10.3389/fonc.2023.1199741 -
Frontiers in Pharmacology 2023
PubMed: 37711174
DOI: 10.3389/fphar.2023.1277561 -
Research Square Oct 2023Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their...
Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/), B-cell lymphoma 2 (), and cyclin dependent kinase inhibitors, including . Pharmacogenetic or pharmacological targeting of or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.
PubMed: 37961365
DOI: 10.21203/rs.3.rs-3467812/v1 -
ELife Oct 2023An assistant professor and group leader explains how being diagnosed with autism in her early 40s changed her approach to being a scientist.
An assistant professor and group leader explains how being diagnosed with autism in her early 40s changed her approach to being a scientist.
Topics: Female; Humans; Autistic Disorder; Physicians
PubMed: 37823395
DOI: 10.7554/eLife.93330