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Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Major depressive disorder (MDD) represents a sizable economic burden in Spain. Pharmacogenetic (PGx) screening to guide the choice of antidepressant medication (ADM) in MDD patients yields higher response and remission rates, which could reduce both healthcare and indirect costs. We built a cost-effectiveness probabilistic Markov model with microsimulation using Tree Age Pro 2022, simulating a patient cohort from the SNHS starting ADM for MDD, and comparing PGx screening before starting ADM versus no screening (No PGx). We carried out a probabilistic sensitivity analysis using the Monte Carlo simulation with microsimulation, set for 1000 iterations and 1000 microsimulation trials, both from societal and healthcare provider perspectives, for a time horizon of 3 years. From a societal perspective, the model estimated a mean cost of 3172.85€ and effectiveness of 2.64 quality-adjusted life years (QALYs) for the No PGx strategy, and a mean cost of 1687.02€ and effectiveness of 2.84 QALYs for the PGx strategy. The mean ICER was −7820.56 €/QALY. From a healthcare provider perspective (no indirect costs considered), the mean cost was 662.62€ for the No PGx strategy, and 446.60€ for the PGx strategy. The mean ICER was −1130.16 €/QALY. The heterogeneity of input data from the literature, the need for assumptions of homogeneous distribution of variables and events across population and time, and the inherent limitations of cost-effectiveness analysis should be considered. The model omits combined therapies (ADMs with mood stabilizers, antipsychotics, cognitive behavioral therapy...). PGx screening in MDD prior to ADM start is a dominant strategy in the SNHS. • Treatment failure rates in major depressive disorder are high and contribute to its economic impact • Pharmacogenetics-guided choice of antidepressants lower failure rates, which could reduce the associated economic burden • We analyzed the cost-effectiveness of this strategy with a Markov model • Microsimulation allows for a more accurate simulation of individual patients' characteristics • Pharmacogenetic screening when starting antidepressants is a dominant strategy [ABSTRACT FROM AUTHOR]

Background: Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure‐specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment. Methods: Inclusion of adult populations in English‐written studies. Review‐specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant). Conclusion: These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care. [ABSTRACT FROM AUTHOR]

Purpose: The recognition of adverse drug reactions (ADRs) is an important part of daily clinical work. However, medical education in this field is mostly drug-based and does not address adequately the complexity of this field regarding individual risk factors and polypharmacy. This study investigates the potential of the web-based serious game SeeMe (side-effect exposure—medical education) in pharmacological education of medical students to improve the recognition of relevant ADRs. Methods: One hundred fifty-seven medical students were recruited to evaluate the serious game SeeMe. SeeMe was developed to improve knowledge and recognition of ADRs in clinical practice. Players take on the role of a physician trying to understand fictional patients with ADRs. Before and after an 8-week playing period, an evaluation was carried out through a pre- and post-questionnaire and a pre- and post- knowledge test. Results: The students achieved significantly better results in the knowledge test, as almost twice as many exam-relevant questions were answered correctly (p < 0.001). The serious game had a positive effect on the students' perception of the importance of ADRs. Conclusion: This study demonstrates the potential of web- and case-based fictional serious games in medical education. The improved recognition of side effects represents a crucial step for education and training in clinical pharmacology. Future versions of the serious game may take this further and focus on training in the treatment of ADRs and their relevance in various healthcare professions. [ABSTRACT FROM AUTHOR]

Objective: This study explores the frequency of human leukocyte antigen (HLA) genes, particularly HLA-B alleles, within the Kuwaiti population. We aim to identify alleles with known associations to adverse drug reactions (ADRs) based on existing literature. We focus on the HLA-B gene due to its well-documented associations with severe cutaneous adverse reactions and the extensive pharmacogenetic research supporting its clinical relevance. Methods: We utilized the HLA-HD tool to extract, annotate, and analyse HLA-B alleles from the exome data of 561 Kuwaiti individuals, sequenced on the Illumina HiSeq platform. HLA typing was conducted using the HLA-HD tool with a reference panel from the IPD-IMGT/HLA database. The major HLA-B pharmacogenetic markers were obtained from the HLA Adverse Drug Reaction Database, focusing on alleles with significant ADR associations in published literature. Results: The distribution of HLA-B alleles in the Kuwaiti population revealed that the most frequent alleles were HLA-B*50:01 (10.52%), HLA-B*51:01 (9.89%), HLA-B*08:01 (6.06%), HLA-B*52:01 (4.55%), HLA-B*18:01 (3.92%), and HLAB* 41:01 (3.65%). Notably, alleles HLA-B*13:01, HLA-B*13:02, HLA-B*15:02, HLA-B*15:13, HLA-B*35:02, HLA-B*35:05, HLA-B*38:01, HLA-B*40:02, HLAB* 44:03, HLA-B*51:01, HLA-B*57:01 and HLA-B*58:01 were identified with known associations to various ADRs. For example, HLA-B*51:01 was associated with clindamycin, phenobarbital, and phenytoin, and was found in 18% of individuals. Conclusion: Our study enriches the regional genetic landscape by delineating HLA-B allele variations within Kuwait and across the Arabian Peninsula. This genetic insight, along with the identification of markers previously linked to drug hypersensitivity, provides a foundation for future pharmacogenetic research and potential personalized medicine strategies in the region. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacogenetics (PGx) holds promise for optimizing psychotropic medication use, with CYP2D6 and CYP2C19 identified as key genes in antidepressant treatment. However, few studies have explored the genetic variants of these genes in real-world settings for patients experiencing ineffectiveness or adverse drug reactions (ADRs) to antidepressants. Methods: This case series includes 40 patients who underwent PGx testing due to antidepressant ineffectiveness or ADRs between June 2020 and April 2022. We describe the patients' demographic, clinical, and genetic characteristics and assess the value of PGx testing based on feedback from their psychiatrists. Results: The most common diagnoses were major depressive disorder (60.0%) and post-traumatic stress disorder (30.0%). Ineffectiveness was reported in 65.0% of patients, ADRs in 2.5%, and both in 32.5%. The antidepressants involved included SSRIs (45.0%), SNRIs (27.5%), atypical antidepressants (20.0%), and tricyclics (17.5%). Only 17.5% of patients had normal CYP2D6 and CYP2C19 metabolic activity. Actionable genetic variants were identified in 22.0% of CYP2D6/CYP2C19-antidepressant-response pairs. PGx recommendations were followed in 92.7% of cases, with significant improvement in ADRs reported in 71.4% of patients and efficacy improvement in 79.5%. Discussion: Our findings suggest that PGx testing can guide prescribing decisions for patients with antidepressant ineffectiveness or ADRs. The relatively high prevalence of genetic variants affecting pharmacokinetics supports the broader adoption of PGx testing in psychiatric practice. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory factors released during severe coronavirus disease-19 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known to influence drug exposure, but data on the effect of mild infection are few. Here we describe for the first time an increase in plasma imatinib and norimatinib concentrations observed in a series of 5 patients treated with imatinib for gastrointestinal stromal tumor (GIST) after mild COVID-19. Methods: The patients were undergoing routine therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) analyses of polymorphisms in genes involved in imatinib metabolism and transport (CYP3A4, CYP3A5, ABCB1, and ABCG2) when SARS-CoV-2 infection occurred. Imatinib and its active metabolite norimatinib concentrations were determined at Ctrough using a validated LCMS/MS method. PGx analyses were performed by KASP genotyping assays on a Real-Time PCR system. All patients received imatinib 400 mg/day. Case 1 was prospectively monitored. Cases 2-5 were identified retrospectively Results: On average, imatinib Ctrough increased significantly by 70% during COVID-19, whereas norimatinib showed a 44% increase compared with pre-COVID-19 levels. Elevated plasma imatinib concentrations persisted up to 6 months after infection remission. In 3 cases, this increase reflected the occurrence or worsening of imatinib side effects. Conclusion: This case-series highlights the clinical impact of SARS-CoV-2 infection on the management of patients with GIST treated with imatinib. [ABSTRACT FROM AUTHOR]

Background: There is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram. Methods: The patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21). Results: At the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response. Conclusions: These findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy. [ABSTRACT FROM AUTHOR]

Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The CYP3A5*3 variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also proven to be influential, especially in CYP3A5 non-expressor patients. The aim of this study is to evaluate the influence of genetic polymorphisms in TAC therapy in a cohort of Spanish transplant recipients. Genetic analysis including ten polymorphic variants was performed, and demographic and clinical data and pharmacotherapy of 26 patients were analyzed. No significant differences were found in weight-adjusted dose between CYP3A5 expressors and non-expressors (0.047 mg/kg vs. 0.044 mg/kg), while they were found for carriers of the CYP3A4*1B allele (0.101 mg/kg; p < 0.05). The results showed that patients with at least one CYP3A4*1B allele had a higher TAC dose and lower blood concentration. Dose-adjusted TAC blood levels were also lower in CYP3A4*1B carriers compared to non-carriers (0.72 ng/mL/mg vs. 2.88 ng/mL/mg). These results support the independence of CYP3A5*3 and CYP3A4*1B variants as determinants of dose requirements despite the linkage disequilibrium present between the two. The variability in genotype frequency between ethnicities may be responsible for the discrepancy found between studies. [ABSTRACT FROM AUTHOR]

The possibility of using the same genotyping technology (TaqMan) for all the genetic tests included in the new Spanish pharmacogenomics portfolio should enable the application of a multigenotyping platform to obtain a whole pharmacogenomics profile. However, HLA-typing is usually performed with other technologies and needs to be adapted to TaqMan assays. Our aim was to establish a set of TaqMan assays for correct typing of HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01. Therefore, we searched for and selected SNVs described in different populations as surrogate markers for these HLA alleles, designed TaqMan assays, and tested in a set of samples with known HLA-A and HLA-B. HLA-A*31:01 was correctly typed with a combination of rs1061235 and rs17179220 (PPV 100%, 95% CI 84.6–100-%; NPV 100%, 95% CI 96.5–100.0%), HLA-B*15:02 with rs10484555 (PPV 100%, 95% CI 69.2–100.0%; NPV 100%, 95% CI 96.8–100.0%) and rs144012689 (PPV 100%, 95% CI 69.2–100.0%; NPV 100%, 95% CI 96.8–100.0%), and HLA-B*57:01 with rs2395029 (PPV 99.5%, 95% CI 72.9–99.3%; NPV 99.5%, 95% CI 98.3–100.0%). HLA-B*58:01 was typed using two allele-specific TaqMan probes mixed with a ß-Globin reference and treated as a genotyping assay (PPV 100.0%, 95% CI 81.5–100.0%; NPV 100%, 95% CI 96.8–100.0%). In conclusion, we demonstrated a clinically useful way to type HLA-A and HLA-B alleles included in the Spanish pharmacogenomics portfolio using TaqMan assays. [ABSTRACT FROM AUTHOR]

Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort. In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined. PGS for MDD was significantly associated with disorder status (NkR2 = 2.48 %, p < 1*10−12), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR. The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS). The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes. • Polygenic risk for MDD was higher in EMC patients than in population-based controls. • Depressive episodes might be linked with higher genetic burden for the disorder. • No significant association between ADR-PGS and treatment response could be found. [ABSTRACT FROM AUTHOR]

Introduction: In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population. Method: Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations. Results: In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans. Conclusion: These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.We prospectively enrolled 63 stable adult kidney‐transplanted patients and collected dense (12‐h, n = 18) or sparse (4‐h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography‐mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.Tacrolimus whole blood concentrations were well described using a two‐compartment pharmacokinetic model with a lag‐time and first‐order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non‐expressors and NR1I2‐25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively.Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies. [ABSTRACT FROM AUTHOR]

Pharmacogenomic (PGx) testing can help personalise psychiatric prescribing and improve on the currently adopted trial-and-error prescribing approach. However, widespread implementation is yet to occur. Understanding factors influencing implementation is pertinent to the psychiatric PGx field. Normalisation Process Theory (NPT) seeks to understand the work involved during intervention implementation and is used by this review (PROSPERO: CRD42023399926) to explore factors influencing PGx implementation in psychiatry. Four databases were systematically searched for relevant records and assessed for eligibility following PRISMA guidance. The QuADS tool was applied during quality assessment of included records. Using an abductive approach to codebook thematic analysis, barrier and facilitator themes were developed using NPT as a theoretical framework. Twenty-nine records were included in the data synthesis. Key barrier themes included a PGx knowledge gap, a lack of consensus in policy and guidance, and uncertainty towards the use of PGx. Facilitator themes included an interest in PGx use as a new and improved approach to prescribing, a desire for a multidisciplinary approach to PGx implementation, and the importance of fostering a climate for PGx implementation. Using NPT, this novel review systematically summarises the literature in the psychiatric PGx implementation field. The findings highlight a need to develop national policies on using PGx, and an education and training workforce plan for mental health professionals. By understanding factors influencing implementation, the findings help to address the psychiatric PGx implementation gap. This helps move clinical practice closer towards a personalised psychotropic prescribing approach and associated improvements in patient outcomes. Future policy and research should focus on the appraisal of PGx implementation in psychiatry and the role of pharmacists in PGx service design, implementation, and delivery. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, it is not metabolized, and it is excreted by the kidney. Although interindividual variability in metformin pharmacokinetics is documented in the Mexican population, its pharmacogenomics is still underexplored. We aimed to identify variants in metformin SLC transporter genes associated with metformin PK and response in Mexican patients. Methods: Using exome data from 2217 Mexican adults, we identified 86 biallelic SNVs in the eight known genes encoding SLC transporters, with a minor allele frequency ≥ 1%, which were analyzed in an inadequate glycemic control (IGC) association study in T2D metformin treated patients. Metformin PK was evaluated in a pediatric cohort and the effect of associated SNVs was correlated. Results: Functional annotation classified two SNVs as pathogenic. The association study revealed two blocks associated with IGC. These haplotypes comprise rs622591, rs4646272, rs4646273, and rs4646276 in SLC22A1; and rs1810126 and rs668871 in SLC22A3. PK profiles revealed that homozygotes of the SLC22A1 haplotype reached lower plasma metformin concentrations 2 h post administration than the other groups. Conclusions: Our findings highlight the potential of pharmacogenomics studies to enhance precision medicine, which may involve dosage adjustments or the exploration of alternative therapeutic options. These hold significant implications for public health, particularly in populations with a high susceptibility to develop metabolic diseases, such as Latin Americans. [ABSTRACT FROM AUTHOR]

Combination antiretroviral therapy (ART) with at least three different drugs has become the standard of care for people with HIV (PWH) due to its exceptional effectiveness in viral suppression. However, many ART drugs have been reported to associate with neuropsychiatric adverse effects including depression, especially when certain genetic polymorphisms exist. Pharmacogenetics is an important consideration for administering combination ART as it may influence drug efficacy and increase risk for neuropsychiatric conditions. Large-scale longitudinal HIV databases provide researchers opportunities to investigate the pharmacogenetics of combination ART in a data-driven manner. However, with more than 30 FDA-approved ART drugs, the interplay between the large number of possible ART drug combinations and genetic polymorphisms imposes statistical modeling challenges. We develop a Bayesian approach to examine the longitudinal effects of combination ART and their interactions with genetic polymorphisms on depressive symptoms in PWH. The proposed method utilizes a Gaussian process with a composite kernel function to capture the longitudinal combination ART effects by directly incorporating individuals' treatment histories, and a Bayesian classification and regression tree to account for individual heterogeneity. Through both simulation studies and an application to a dataset from the Women's Interagency HIV Study, we demonstrate the clinical utility of the proposed approach in investigating the pharmacogenetics of combination ART and assisting physicians to make effective individualized treatment decisions that can improve health outcomes for PWH. [ABSTRACT FROM AUTHOR]

Precision medicine presents an opportunity to use novel, data‐driven strategies to improve patient care. The field of precision medicine has undergone many advancements over the past few years. It has moved beyond incorporation of individualized genetic risk into medical decision‐making to include multiple other factors such as unique social, demographic, behavioral, and clinical characteristics. Geriatric medicine stands to benefit heavily from the integration of precision medicine into its standard practices. Older adults, compared with other populations, have high clinical and biological heterogeneity that can alter the risks and benefits of different approaches to patient care. These factors have not been routinely considered previously by geriatricians. Yet, geriatricians' ability to address older adults' baseline heterogeneity is increasingly recognized as a cornerstone of delivering quality care in a geriatric medical practice. Given the shared focus of individualized decision‐making, precision medicine is a natural fit for geriatric medicine. This manuscript provides, via cases and discussion, examples that illustrate how precision medicine can improve the care of our older patients today. We will share specific and existing tools and evidence, and review the existing multilevel barriers to further incorporate and implement these tools into clinical practice. We propose methods to address these barriers and to help realize the full potential of precision medicine for the care of older adults. We conclude with a brief discussion of potential future directions of research of precision medicine in the care of older adults. [ABSTRACT FROM AUTHOR]

With the continuous development of genetics in healthcare, there has been a significant contribution to the development of precision medicine, which is ultimately aimed at improving the care of patients. Generally, drug treatments used in Oncology are characterized by a narrow therapeutic range and by their potential toxicity. Knowledge of pharmacogenomics and pharmacogenetics can be very useful in the area of Oncology, as they constitute additional tools that can help to individualize patients' treatment. This work includes a description of some genes that have been revealed to be useful in the field of Oncology, as they play a role in drug prescription and in the prediction of treatment response. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real‐world population. Methods: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N‐desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype‐predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration‐to‐dose (CD) ratio and metabolite‐to‐parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal–Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. Results: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P <.001), 28% in CYP2C19 IMs (P <.001) and 31% in CYP2C19 PMs (P =.04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. Conclusions: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone. [ABSTRACT FROM AUTHOR]

Background and Aim: Among the cardiovascular diseases (CVDs), heart failure, hypertension, and myocardial infarction are associated with the greatest number of disability‐adjusted life years due to lifestyle changes and the failure of therapeutic approaches, especially the one‐size‐fits‐all interventions. As a result, there has been advances in defining genetic variants responsible for different responses to cardiovascular drugs such as antiplatelets, anticoagulants, statins, and beta‐blockers, which has led to their usage in guiding treatment plans. This study comprehensively reviews the current state‐of‐the‐art potential of pharmacogenomics in dramatically altering CVD treatment. It stresses the applicability of pharmacogenomic technology, the threats associated with its adoption in the clinical setting, and proffers relevant solutions. Methods: Literature search strategies were used to retrieve articles from various databases: PubMed, Google Scholar, and EBSCOhost. Articles with information relevant to pharmacogenomics, DNA variants, cardiovascular diseases, sequencing techniques, and drug responses were reviewed and analyzed. Results: DNA‐based technologies such as next generation sequencing, whole genome sequencing, whole exome sequencing, and targeted segment sequencing can identify variants in the human genome. This has played a substantial role in identifying different genetic variants governing the poor response and adverse effects associated with cardiovascular drugs. Thus, this has reduced patients' number of emergency visits and hospitalization. Conclusion: Despite the emergence of pharmacogenomics, its implementation has been threatened by factors including patient compliance and a low adoption rate by clinicians. Education and training programs targeting both healthcare professionals and patients should be established to increase the acceptance and application of the emerging pharmacogenomic technologies in reducing the burden of CVDs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods: The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results: The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions: It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding. [ABSTRACT FROM AUTHOR]

Background: In the context of the cytokine storm the takes place in severe COVID-19 patients, the Interleukin 6 (IL6) pathway emerges as one of the key pathways involved in the pathogenesis of this hyperinflammatory state. The strategy of blocking the inflammatory storm by targeting the IL6 is a promising therapy to mitigate mortality. The use of Tocilizumab was recommended by the World Health Organization (WHO) to treat severe COVID-19 patients. However, the efficacy of Tocilizumab is variable. We hypothesize that the genetic background could be behind the efficacy of Tocilizumab in terms of mortality. Methods: We performed a targeted-next generation sequencing of 287 genes, of which 264 belong to a community panel of ThermoFisher for the study of genetic causes of primary immunodeficiency disorders, and 23 additional genes mostly related to inflammation, not included in the original community panel. This panel was sequenced in an initial cohort of 425 COVID-19 patients, of which 232 were treated with Tocilizumab and standard therapy, and 193 with standard therapy only. Selected genetic variants were genotyped by single base extension in additional 245 patients (95 treated with Tocilizumab and 150 non-treated with Tocilizumab). Appropriate statistical analyses and internal validation, including logistic regression models, with the interaction between Tocilizumab and genetic variants, were applied to assess the impact of these genetic variants in the efficacy of Tocilizumab in terms of mortality. Results: Age (p < 0.001) and cardiovascular disease (p < 0.001) are risk factors for mortality in COVID-19 patients. The presence of GG and TT genotypes at IL10Rβ (rs2834167) and IL1β (rs1143633) genes significantly associates with a reduced risk of mortality in patients treated with Tocilizumab (OR = 0.111; 95%CI = 0.015-0.829; p = 0.010 and OR = 0.378; 95%CI = 0.154-0.924; p = 0.028 respectively). The presence of CC genotype at IL1RN (rs2234679) significantly associates with an increased risk of mortality, but only in patients not treated with Tocilizumab (OR = 3.200; 95%CI = 1.512-6.771; p = 0.002). Exhaustive internal validation using a bootstrap method (B = 500 replicates) validated the accuracy of the predictive models. Conclusion: We developed a series of predictive models based on three genotypes in genes with a strong implication in the etiopathogenesis of COVID-19 disease capable of predicting the risk of mortality in patients treated with Tocilizumab. [ABSTRACT FROM AUTHOR]

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication. [ABSTRACT FROM AUTHOR]

Introduction: Genomic healthcare applications have relevance to all healthcare professionals including nursing, and most evidence‐based clinical applications impact the quality and safety of healthcare. To guide nursing genomic competency initiatives, the Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics were established through a process of consensus in 2005. A 2009 update incorporated outcome indicators consisting of specific areas of knowledge and clinical performance indicators, to help support academic integration. Almost 20 years have elapsed since these competencies were first established, yet incorporating the competencies into general and specialty scope and standards of nursing practice is inconsistent, competency integration into curricula is highly uneven, continuing education in genomics for nurses is limited, and the genomic capacity of the nursing workforce remains low. These deficits have persisted despite substantial advances in genomic technology which substantially reduced costs and increased evidence‐based clinical applications, including direct to consumer genomic tests, the integration of genomics into evidence‐based guidelines, and evidence that genomics impacts the quality and safety of healthcare. Design: The aim of this project was to update and achieve consensus on genomic competencies applicable to all registered nurses. This was a mixed methods study. Methods: The update to the competencies was performed based first on a literature review to update the competencies based on the current state of the evidence. Using the updated content, a modified Delphi study was conducted with registered nurse panelists from clinical, academic, and research settings. Once consensus was achieved, the competencies were made available through the American Nurses Association for public comment. Public comments were then reviewed and integrated as needed. Results: The literature review resulted in a transition from genetics to genomics, given the reduction in costs, which resulted in an expansion of the scope of testing in both the germline and somatic contexts. Two Delphi rounds were required to reach consensus prior to the public comment period. Public comments were solicited through the American Nurses Association, and each comment was reviewed by the authors and addressed as indicated. Conclusion: The Essentials of Genomic Nursing: Competencies and Outcome Indicators constitute the minimum competency in genomics required of all registered nurses regardless of the level of academic training, role, or specialty. Clinical Relevance: Evidence‐based genomic applications span the entire healthcare continuum and, therefore, are relevant for all registered nurses regardless of academic training, role, practice setting, or clinical expertise. These competencies serve as the guide for the minimum requirements for registered nurse practice as well as guide curricula and continuing education for all registered nurses, including but not limited to administrators, educators, nursing leaders, practicing nurses, and researchers. [ABSTRACT FROM AUTHOR]

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature. [ABSTRACT FROM AUTHOR]

Catechol-O-methyltransferase inhibitors (COMT-Is) have significantly improved the quality of life and symptom management for those at advanced stages of Parkinson's Disease (PD). Given that PD is one of the fastest-growing neurodegenerative diseases worldwide, there is a need to establish a clear framework for the systematic distribution of COMT-Is, considering inter-individual and intra-individual variations in patient response. One major barrier to this is the underrepresentation of ethnic minority participants in clinical trials investigating COMT-Is. To investigate this, we performed a narrative review. We searched PubMed for clinical trials investigating COMT-Is in patients with PD and examined the ethnic diversity of cohorts. A total of 63 articles were identified, with 34 trials found to match our inclusion criteria. Among the 34 trials meeting our inclusion criteria, only 8 reported participants' ethnic backgrounds. Our findings reveal a consistent underrepresentation of ethnic minority groups in trials investigating COMT-Is in PD cohorts—a trend that reflects broader concerns across clinical research. In this review, we explore potential reasons for the underrepresentation of ethnic minorities in clinical trials and propose strategies to address this issue. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia represents the most prevalent childhood cancer. Modern chemotherapy has significantly improved outcomes, achieving EFS rates of 80% and OS rates nearing 90% in developed nations, while in developing regions, rates remain below 50%, highlighting disparities, and this difference is due to several factors. Genetic variability plays a role in these drug response disparities, presenting single-nucleotide variations (SNVs). Pharmacogenetic research aims to pinpoint these SNVs early in treatment to predict specific drug responses effectively. This review aims to explore advancements in pharmacogenetics associated with asparaginase (ASNase). ASNase plays a crucial role in the treatment of ALL and is available in three formulations: E. coli, Erwinia, and PEG ASNase. ASNase therapy presents challenges due to adverse effects, like hypersensitivity reactions. Identifying predictive markers for hypersensitivity development beforehand is crucial for optimizing treatments. Several pharmacogenetic studies have investigated the association between SNVs and the risk of hypersensitivity. Key genes include GRIA1, NFATC2, CNTO3, ARHGAP28, MYBBP1A, and HLA. Studies have highlighted associations between SNVs within these genes and hypersensitivity reactions. Notably, most pharmacogenetic investigations of hypersensitivity have focused on patients treated with E. coli, emphasizing the need for broader exploration across different formulations. Future research investigating these variants holds promise for advancing our understanding of ASNase's pharmacogenetics. [ABSTRACT FROM AUTHOR]

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (Cmax/DW)), elimination (terminal half-life (T1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and Cmax/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and Cmax/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, Cmax, and CL/F of 5-HMT, which should be confirmed in other studies. [ABSTRACT FROM AUTHOR]

Background/Objectives: Epilepsy is a brain disease with both environmental and genetic inputs. Ion channel dysfunction seems to be of great significance for abnormal neuronal behavior during epileptic seizures. Within neurons, the voltage-gated sodium channels are crucial proteins contributing to the initiation and propagation of action potentials. The voltage-gated sodium channel α subunit 1 (SCN1A) gene encodes for the α subunit of a voltage-gated ion channel. The aim of the study was to investigate the relation of two common SCN1A variants, i.e., rs3812718 and rs2298771, with distinct epileptic phenotypes in a South-Eastern European population. Methods: DNA was extracted from 214 unrelated participants with focal onset, focal to bilateral tonic–clonic, or generalized onset epileptic seizures and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Statistical analysis of the results was performed using IBM SPSS Statistics software (version 29.0 for Windows). Results: Genotype frequency distribution analysis indicated an association for the A-allele-containing genotypes of both rs3812718 and rs2298771 polymorphisms of SCN1A with generalized onset seizures and focal to bilateral tonic–clonic seizures versus focal onset seizures. Conclusions: Consequently, the study provides evidence that supports a potential association of the investigated SCN1A polymorphisms with distinct seizure subtype susceptibility in South-Eastern Europeans. [ABSTRACT FROM AUTHOR]

Background: The enzyme expression (i.e. phenotype) of the Cytochrome P450 2D6 (CYP2D6) gene is highly relevant to the metabolism of psychotropic medications, and therefore to precision medicine (i.e. personalised prescribing). Aims: This review aims to assess the improvement in CYP2D6 phenotyping sensitivity (IPS) and accuracy (IPA) offered by long-read sequencing (LRS), a new genetic testing technology. Methods: Human DNA samples that underwent LRS genotyping of CYP2D6 in published, peer-reviewed clinical research were eligible for inclusion. A systematic literature search was conducted until 30 September 2023. CYP2D6 genotypes were translated into phenotypes using the international consensus method. IPS was the percentage of non-normal LRS CYP2D6 phenotypes undetectable with FDA-approved testing (AmpliChip). IPA was the percentage of LRS CYP2D6 phenotypes mischaracterised by non-LRS genetic tests (for samples with LRS and non-LRS data). Results: Six studies and 1411 samples were included. In a meta-analysis of four studies, IPS was 10% overall (95% CI = (2, 18); n = 1385), 20% amongst Oceanians (95% CI = (17, 23); n = 582) and 2% amongst Europeans (95% CI = (1, 4); n = 803). IPA was 4% in a large European cohort (95% CI = (2, 7); n = 567). When LRS was used selectively (e.g. for novel or complex CYP2D6 genotypes), very high figures were observed for IPS (e.g. 88%; 95% CI = (72, 100); n = 17; country = Japan) and IPA (e.g. 76%; 95% CI = (55, 98); n = 17; country = Japan). Conclusions: LRS improves CYP2D6 phenotyping compared to established genetic tests, particularly amongst Oceanian and Japanese individuals, and those with novel or complex genotypes. LRS may therefore assist in optimising personalised prescribing of psychotropic medications. Further research is needed to determine associated clinical benefits, such as increased medication safety and efficacy. [ABSTRACT FROM AUTHOR]

Ramipril is an angiotensin‐converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty‐nine healthy volunteers who had participated in a single‐dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype‐informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7‐fold higher dose/weight‐corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p‐value [puv] < 0.001, multivariate p‐value [pmv] < 0.001, β = 0.533, R2 = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6‐fold higher AUC/DW than those with the NF phenotype (puv = 0.011, pmv < 0.001, β = 0.259, R2 = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance. [ABSTRACT FROM AUTHOR]

Background/Aim: Endocrine therapy is the standard treatment for hormone receptor-positive (HR+) breast cancer (BC). Yet, it is accompanied by treatment-related toxicities, leading to poor treatment adherence, high relapse, and low rates of survival. While pharmacogenomic variants have the potential to guide personalized treatment, their predictive value is inconsistent across published studies. Materials and Methods: To systematically assess the literature's current landscape of pharmacogenomics of endocrine therapy-related adverse drug effects, systematic searches in MEDLINE, Embase, Cochrane CENTRAL, Google Scholar and PharmGKB databases were conducted. Results: We identified 87 articles. Substantial heterogeneity and variability in pharmacogenomic effects were evident across studies, with many using data from the same cohorts and predominantly focusing on the Caucasian population and postmenopausal women. Meta-analyses revealed Factor V Leiden mutation as a predictor of thromboembolic events in tamoxifen-treated women (p<0.0001). Meta-analyses also found that rs7984870 and rs2234693 were associated with musculoskeletal toxicities in postmenopausal women receiving aromatase inhibitors (p<0.0001 and p<0.0001, respectively). Conclusion: Overall, the current body of evidence regarding the potential role of pharmacogenomics in endocrine therapy-related toxicity in BC remains largely inconclusive. Key concerns include the heterogeneity in toxicity definitions, lack of consideration for genotype-treatment interactions, and the failure to account for multiple testing. The review underscores the necessity for larger and well-designed studies, particularly with the inclusion of premenopausal women and non-Caucasian populations. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is an anti-folate chemotherapeutic agent that is considered to be a gold standard in Acute Lymphoblastic Leukemia (ALL) therapy. Nevertheless, toxicities induced mainly due to high doses of MTX are still a challenge for clinical practice. MTX pharmacogenetics implicate various genes as predictors of MTX toxicity, especially those that participate in MTX intake like solute carrier family 19 member 1 (SLC19A1). The aim of the present study was to evaluate the association between SLC19A1 polymorphisms and its regulatory miRNAs with MTX toxicity in children with ALL. A total of 86 children with ALL were included in this study and were all genotyped for rs2838958, rs1051266 and rs1131596 SLC19A1 polymorphisms as well as the rs56292801 polymorphism of miR-5189. Patients were followed up (48, 72 and 96 h) after treatment with MTX in order to evaluate the presence of MTX-associated adverse events. Our results indicate that there is a statistically significant correlation between the rs1131596 SLC19A1 polymorphism and the development of MTX-induced hepatotoxicity (p = 0.03), but there is no significant association between any of the studied polymorphisms and mucositis or other side effects, such as nausea, emesis, diarrhea, neutropenia, skin rash and infections. In addition, when genotype TT of rs1131596 and genotype AA of rs56292801 are both present in a patient then there is a higher risk of developing severe hepatotoxicity (p = 0.0104).

Yudisia Ausi,1,2 Melisa Intan Barliana,2,3 Maarten J Postma,3,4 Auliya A Suwantika3,5 1Doctor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia; 2Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia; 3Center of Excellence for Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia; 4Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; 5Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, IndonesiaCorrespondence: Auliya A Suwantika, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jalan Raya Bandung Sumedang KM 21 Jatinangor, Sumedang, 45363, Indonesia, Tel +62 22 84288828, Email auliya@unpad.ac.idAbstract: Pharmacogenetics is a promising approach in future personalized medicine. This field holds excellent prospects for healthcare quality acceleration. It promotes the transition to the precision medicine era, whereby a health treatment is driven by a deeper understanding of individual characteristics by interpreting the underlying genomic variation. Pharmacogenetics has been developing rapidly since the human genome project. Many pharmacogenetics studies have shown the association between genetic variants and therapy outcomes. Several pharmacogenetics working groups have recommended guidelines for the clinical application of pharmacogenetics. However, the development of pharmacogenetics in low- and middle-income countries (LMICs) is still retarded behind. The problems mainly include clinical evidence, technology, policy and regulation, and human resources. Currently, available genome and drug effect data in LMICs are scarce. Pharmacogenetics development should be escalated with evidence proof through research collaboration across countries. The challenges of pharmacogenetics implementation are discussed comprehensively in this article, along with the prospect of pharmacogenetics-guided personalized medicine in developed countries. Stepwise is expected to help the researchers and stakeholders define the problem that hindered the pharmacogenetics application.Keywords: pharmacogenetics, implementation, LMICs, personalized medicine

Abstract Background There is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram. Methods The patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21). Results At the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response. Conclusions These findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy.

Abstract While significant strides have been made in understanding pharmacogenetics (PGx) and gene-drug interactions, there remains limited characterization of population-level PGx variation. This study aims to comprehensively profile global star alleles (haplotype patterns) and phenotype frequencies in 58 pharmacogenes associated with drug absorption, distribution, metabolism, and excretion. PyPGx, a star-allele calling tool, was employed to identify star alleles within high-coverage whole genome sequencing (WGS) data from the 1000 Genomes Project (N = 2504; 26 global populations). This process involved detecting structural variants (SVs), such as gene deletions, duplications, hybrids, as well as single nucleotide variants and insertion-deletion variants. The majority of our PyPGx calls for star alleles and phenotype frequencies aligned with the Pharmacogenomics Knowledge Base, although notable population-specific frequencies differed at least twofold. Validation efforts confirmed known SVs while uncovering several novel SVs currently undefined as star alleles. Additionally, we identified 210 small nucleotide variants associated with severe functional consequences that are not defined as star alleles. The study serves as a valuable resource, providing updated population-level star allele and phenotype frequencies while incorporating SVs. It also highlights the burgeoning potential of cost-effective WGS for PGx genotyping, offering invaluable insights to improve tailored drug therapies across diverse populations.

Metabolic syndrome (MetS) presents a significant global health challenge, characterized by a cluster of metabolic alterations including obesity, hypertension, insulin resistance/dysglycemia, and atherogenic dyslipidemia. Advances in understanding and pharmacotherapy have added complexity to MetS management, particularly concerning drug interactions and pharmacogenetic variations. Limited literature exists on drug–drug–gene interactions (DDGIs) and drug–drug–transporter gene interactions (DDTGIs), which can significantly impact pharmacokinetics and pharmacodynamics, affecting treatment outcomes. This narrative review aims to address the following three key objectives: firstly, shedding a light on the PK metabolism, transport, and the pharmacogenetics (PGx) of medicines most commonly used in the MetS setting (relevant lipid-lowering drugs, antihypertensives and antihyperglycemics agents); secondly, exemplifying potential clinically relevant pharmacokinetic drug interactions, including drug–drug interactions, DDGIs, and DDTGIs; and, thirdly, describing and discussing their potential roles in clinical practice. This narrative review includes relevant information found with the use of interaction checkers, pharmacogenetic databases, clinical pharmacogenetic practice guidelines, and literature sources, guided by evidence-based medicine principles.

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature.

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.

Currently, 30–50 % of individuals with depression and 40 % with anxiety—collectively referred to as common mental disorders (CMDs), exhibit inadequate responses to antidepressant treatments. To assess the effectiveness and safety of drug-metabolizing enzyme pharmacogenetic variation informed treatment (PGxIT) versus usual antidepressant treatment (UT) in patients with CMDs. A literature search was conducted in the MEDLINE, Scopus, and Cochrane Library databases from inception until January 30, 2024. Studies were selected based on CMD diagnoses, reporting on the genetic variations of drug-metabolizing enzyme (DME) genes in relation to antidepressants, involving PGxIT and UT groups with human subjects, and published in English. Data extraction and quality assessment were performed independently by two authors. A pooled risk ratio (RR) with 95 % CI was estimated using both random and fixed-effect models, and heterogeneity was assessed using Cochran's Q test and the I2 statistic. The publication bias of eligible studies was assessed using post hoc Doi plots and the LFK index. This systematic review included 18 studies (n = 7021). The PGxIT demonstrated greater efficacy in the remission of symptoms of depressive disorder at 8 weeks (RR 1.523 [95 % CI: 1.255–1.843]; I2 = 48 %) and 12 weeks (RR 1.631 [95 % CI: 1.001–2.657]; I2 = 86 %; p < 0.01), and symptoms of anxiety disorder compared to UT. Additionally, the risk of adverse drug events (ADEs) was significantly lower in the PGxIT group (RR = 0.65 [95 % CI: 0.52–0.82]; I2 = 0 %) than in the UT group. The certainty of evidence for both outcomes was moderate. This systematic review and meta-analysis suggest that pharmacogenetically guided antidepressant treatment, based on genetic variation in drug-metabolizing enzymes, is associated with superior efficacy in the remission of symptoms for patients with depressive disorders and a reduction in ADEs compared to usual treatment and the findings of the systematic review for remission in anxiety disorders indicate that, PGx guided treatment is also associated with increased remission of symptoms in anxiety disorders compared to usual treatment. • Up to 30-50% of depression and 40% of anxiety patients show inadequate responses to standard antidepressant treatments. • PGxIT improved depressive disorder remission at 8 and 12 weeks and showed better safety with fewer adverse drug events over UT. • PGxIT also enhanced anxiety disorder remission, but more research is needed to confirm its effectiveness. • Moderate evidence supports PGxIT's benefits for depression, with potential for broader clinical application. [ABSTRACT FROM AUTHOR]

Objective: Upper gastrointestinal bleeding (UGIB) has been identified as a potential adverse drug reaction associated with the use of low-dose aspirin (LDA). This study aimed to investigate the relationship between variants in the TBXA2R gene, which is involved in platelet aggregation, and the risk of UGIB in patients with cardiovascular diseases treated with LDA. Methods: A case-control study was conducted at a Brazilian hospital complex. Three groups were defined: (1) case group (n = 50): patients with cardiovascular disease who used LDA and were diagnosed with UGIB of non-variceal etiology, (2) LDA control group (n = 50): patients with cardiovascular disease who used LDA without developing UGIB, and (3) healthy control group (n = 189). Data were collected through face-to-face interviews, and blood samples were collected for the analysis of Helicobacter pylori infection and genotyping of 3 genetic variants [rs2238631 (C > T), rs4807491 (A > G), and rs1131882 (A > G)]. Results: The case group had a significantly higher frequency of carriers of the rs4807491.G allele compared to the control group of LDA users (P -value =.004). No significant difference was observed in the proportion of carriers of the rs2238631.T and 1131882.G variants between the studied groups. Carriers of rs2238631.T (OR: 4.515, 95% CI: 1.37-14.89) and rs4807491.G allele (OR: 3.232, 95% CI: 1.12-9.37) exhibited a higher risk of UGIB. Conclusion: These findings suggest that the presence of the rs2238631 and rs4807491 variant alleles is associates with a 3- to 4-fold increased risk of UGIB in patients with cardiovascular diseases treated with LDA. Future studies with larger sample sizes should confirm these results and to better identify individuals who may benefit from chronic LDA use. [ABSTRACT FROM AUTHOR]

Globally, cardio vascular diseases (CVD) remain the primary cause of morbidity and mortality. Pharmacogenomics (PGxs) has profoundly changed how various drug classes are managed in CVDs. For example, genetic polymorphisms in genes such as SLCO1B1 impact how a person responds to statins such as rosuvastatin and atorvastatin, where as the interindividual variability in the reaction to statins (Fluvastatin)used in lipid-lowering therapy can be partly explained by genetic variations in genes encoding drug-metabolizing enzymes such cytochrome P450 and transporters like OATP1B1. Similarly, in antiplatelet therapy, polymorphisms in CYP2C19 affect clopidogrel metabolism, influencing its efficacy in preventing thrombotic events. Genes such as CYP2C9 and VKORC1 are crucial for the metabolism and response to acenocoumarol and warfarin during anticoagulant therapy and monitoring bleeding risk. Genetic variations in CYP2D6 affect the metabolism and effectiveness of propafenone and metoprolol. Understanding the PGx presumptions of these cardiovascular drugs may help develop personalized treatment strategies that lower the possibility of adverse drug reactions, obtain desired therapeutic outcomes, and improve patient compliance and safety with respect to each patient’s unique genetic makeup.

Abstract Background The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 − 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P

Abstract Background Human immunodeficiency virus (HIV) and tuberculosis (TB) are major contributors to morbidity and mortality in sub-Saharan Africa including Cameroon. Pharmacogenetic variants could serve as predictors of drug-induced hepatotoxicity (DIH), in patients with TB co-infected with HIV. We evaluated the occurrence of DIH and pharmacogenetic variants in Cameroonian patients. Methods Treatment-naïve patients with HIV, TB or TB/HIV co-infection were recruited at three hospitals in Cameroon, between September 2018 and November 2019. Appropriate treatment was initiated, and patients followed up for 12 weeks to assess DIH. Pharmacogenetic variants were assessed by allele discrimination TaqMan SNP assays. Results Of the 141 treatment naïve patients, the overall incidence of DIH was 38% (53/141). The highest incidence of DIH, 52% (32/61), was observed among HIV patients. Of 32 pharmacogenetic variants, the slow acetylation variants NAT2*5 was associated with a decreased risk of DIH (OR: 0.4; 95%CI: 0.17–0.96; p = 0.038), while NAT2*6 was found to be associated with an increased risk of DIH (OR: 4.2; 95%CI: 1.1–15.2; p = 0.017) among patients treated for TB. Up to 15 SNPs differed in ≥ 5% of allele frequencies among African populations, while 25 SNPs differed in ≥ 5% of the allele frequencies among non-African populations, respectively. Conclusions DIH is an important clinical problem in African patients with TB and HIV. The NAT2*5 and NAT2*6 variants were found to be associated with DIH in the Cameroonian population. Prior screening for the slow acetylation variants NAT2*5 and NAT2*6 may prevent DIH in TB and HIV-coinfected patients.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The β2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

Abstract Pharmacogenetics investigates sequence of genes that affect drug response, enabling personalized medication. This approach reduces drug-induced adverse reactions and improves clinical effectiveness, making it a crucial consideration for personalized medical care. Numerous guidelines, drawn by global consortia and scientific organizations, codify genotype-driven administration for over 120 active substances. As the scientific community acknowledges the benefits of genotype-tailored therapy over traditionally agnostic drug administration, the push for its implementation into Italian healthcare system is gaining momentum. This evolution is influenced by several factors, including the improved access to patient genotypes, the sequencing costs decrease, the growing of large-scale genetic studies, the rising popularity of direct-to-consumer pharmacogenetic tests, and the continuous improvement of pharmacogenetic guidelines. Since EMA (European Medicines Agency) and AIFA (Italian Medicines Agency) provide genotype information on drug leaflet without clear and explicit clinical indications for gene testing, the regulation of pharmacogenetic testing is a pressing matter in Italy. In this manuscript, we have reviewed how to overcome the obstacles in implementing pharmacogenetic testing in the clinical practice of the Italian healthcare system. Our particular emphasis has been on germline testing, given the absence of well-defined national directives in contrast to somatic pharmacogenetics.

INTRODUCTION. The pathogenesis of antibiotic-associated drug-induced liver injury (DILI) in children has not been fully elucidated to date. Certain genotypes in patients increase the probability of developing DILI. Therefore, the identification of pharmacogenetic markers associated with DILI in children is essential.АIM. This study aimed to identify pharmacogenetic biomarkers of new-onset DILI associated with tigecycline and meropenem in children.MATERIALS AND METHODS. This prospective observational study was conducted in the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study analysed the incidence and types of antibiotic-associated adverse drug reactions (ADRs) in 100 critically ill children aged 0 to 17 years (44 boys and 56 girls). Pharmacogenetic testing was performed in children with ADRs (n=30) to identify potential mechanisms involved in the development of their ADRs. The authors isolated and tested DNA from buccal epithelium swabs using the Agena Bioscience iPLEX® PGx Pro-based VeriDose® Core Panel covering 68 single nucleotide polymorphisms (SNPs) or short insertions and deletions (INDELs) and 5 copy number variants (CNVs).RESULTS. The odds of developing DILI associated with meropenem and tigecycline were higher in carriers of the homozygous cytochrome genotype CYP3A5*3/*3 (OR: 12.6; 95% CI: 1.9–79.4, r=6.54, p=0.011) than in patients with the heterozygous genotype CYP3A5*1A/*3. The odds were even higher in patients not carrying the CYP3A5*1A/*3 genotype (OR: 17.14; 95% CI: 1.79–16.3, r=6.24, p=0.013). The detection of the CYP3A5*3/*3 ge­notype had a prognostic accuracy of 76.7%, a sensitivity of 82%, and a specificity of 74% in predicting the risk of DILI associated with meropenem and tigecycline. Moreover, children with DILI carried the heterozygous ge­notype SLCO1B1*1/*5 (rs4149056 polymorphism) more often than children with other adverse reactions ­associated with meropenem and tigecycline (r=9.8, p=0.002).CONCLUSION. The results of this study prove the prognostic significance of the homozygous cytochrome genotype CYP3A*3/*3 as an indicator of a potential risk for developing DILI associated with meropenem and tigecycline in children in critical conditions.The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

Identification of the genetic features that determine a patient’s individual response to a medicinal product and provision of this information to a doctor helps to predict the effectiveness of therapy and the risk of adverse drug reactions. Dmitry A. Sychev — Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Full Professor, Rector of the Russian Medical Academy of Continuous Professional Education — talks about the importance of a personalised approach to selecting medicinal products and methods for their efficacy and safety control.

Background: Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2‐negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. Methods: In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). Results: We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple‐negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. Conclusion: This retrospective, real‐world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes. [ABSTRACT FROM AUTHOR]