Search Results (463)

Background/Objectives: Patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are at high risk for severe disease and treatment-related complications and toxicities. Pharmacogenetic studies suggest that genetic variants can alter the response to several drugs critical to alloHCT outcomes, including tacrolimus and cyclophosphamide, potentially impacting toxicity and treatment outcomes. Methods: To assess the frequency of pharmacogenetic variants in AML/ALL patients undergoing alloHCT, we used a validated 11-gene pharmacogenetic panel in an exploratory descriptive study. We retrospectively genotyped 142 AML/ALL patients including two atypical chronic myeloid leukemia (aCML) patients, ≥18 years, who underwent alloHCT at our center between January 2020 and June 2024. Results obtained from 470 individuals in the Lifelines NEXT population cohort were used as controls. Results: Almost all patients carried at least one pharmacogenetic variant (97.2%), with a mean of 3.2 (standard deviation = 1.5) variants per patient. Variants known to influence tacrolimus metabolism (CYP3A4 and CYP3A5) were present in 26.8% of patients. Variants known to influence cyclophosphamide metabolism (CYP2B6, CYP2C9, CYP2C19) were present in 81.7% of patients. Variant frequencies did not significantly differ from controls. Conclusions: Actionable pharmacogenetic variants are highly prevalent in alloHCT-recipients. Future studies should investigate whether genotype-guided drug selection and dosing could improve outcomes in alloHCT recipients. Full article

Vivipary adversely affects the production process of the cucumber seed industry and greatly limits the popularization of cucumber varieties. Identification of the cucumber seed vivipary phenotype and screening of vivipary-associated genes will provide important theoretical value and practical significance for solving this problem in agricultural production. In this study, cucumber near-isogenic lines with significant differences in vivipary traits (viviparous line F and non-viviparous line BF) were successfully screened and used to construct genetic populations. Bulk segregant analysis (BSA) and QTL-seq were performed to fine-map the major-effect quantitative trait locus associated with vivipary variation. Based on QTL and BSA analyses, CsaV3_3G044640 (designated CsCYP82D47), which encodes a cytochrome P450 family protein, was identified as a candidate gene associated with cucumber vivipary. CsCYP82D47 exhibits obvious tissue specificity and is highly expressed in leaves, sprouts, and seeds. However, no significant difference in CsCYP82D47 expression was detected between viviparous and non-viviparous cucumber materials. Further sequence analysis revealed multiple mutation sites in this gene between different genotypes. Specifically, the CYP82D47 protein in viviparous materials harbours one amino acid insertion (L63) and two missense mutations (M71L and S124L). In addition, the altered leucine residue distribution in viviparous cucumber may enlarge the substrate channel and enhance substrate catalytic efficiency, which may contribute to the vivipary phenotype. In summary, this study identifies a promising candidate gene potentially related to cucumber vivipary, which lays a foundation for further exploration of the molecular mechanism underlying cucumber vivipary and provides a potential genetic resource for cucumber molecular breeding. Full article

Background/Objectives: Kidney graft dysfunction remains a major challenge limiting long-term transplant survival despite advances in immunosuppressive therapy. Cytokine signaling pathways have been implicated in the regulation of alloimmune responses and chronic inflammation, but their contribution to long-term graft function and immunosuppressant pharmacokinetics remains incompletely understood. This study investigated associations among selected cytokine gene polymorphisms (IL-2 −330T>G, IL-6 −174G>C, and IL-10 −1082A>G), biochemical and hematological parameters, and calcineurin inhibitor (tacrolimus and cyclosporine) dosing in kidney transplant recipients. Methods: A total of 394 kidney transplant recipients receiving tacrolimus or cyclosporine were enrolled. Genotyping of IL-2 rs2069762, IL-6 rs1800795 and IL-10 rs1800896 was performed using real-time PCR. Clinical, biochemical, and pharmacokinetic data were analyzed using univariate and multivariate statistical models adjusted for relevant demographic and clinical covariates. Results: IL-2 rs2069762 and IL-6 rs1800795 polymorphisms were not associated with clinically relevant differences in biochemical parameters, calcineurin inhibitor dosing, or transplant outcomes. For IL-10 rs1800896, no statistically significant associations were observed with cyclosporine A blood levels, dose, or C/D ratio. Among tacrolimus-treated patients, the regression model for the C/D ratio was borderline significant (F(2,207) = 3.048, p = 0.050, R² = 0.029). However, the genotype-specific association for the heterozygous GA genotype versus AA was not statistically significant in the unadjusted model (B = −0.462, 95% CI: −0.97 to 0.04, p = 0.072) or after adjustment for age, sex, and time since transplantation (B = −0.450, 95% CI: −0.95 to 0.05, p = 0.078). Although univariate analyses identified associations between IL-10 rs1800896 and selected biochemical parameters, these findings were not confirmed in multivariable models. No significant associations were observed between the analyzed cytokine polymorphisms and graft rejection, graft survival, patient survival, or clinically relevant markers of kidney graft function. Conclusions: The results suggest a possible, although not statistically significant, association between IL-10 rs1800896 and tacrolimus exposure, as assessed by the C/D ratio. This observation should be considered preliminary and interpreted with caution. The lack of CYP3A5 genotyping and functional assessment of IL-10 activity, inflammation, and CYP3A-dependent metabolism further limits the interpretation of this potential association. Larger prospective studies with comprehensive pharmacogenetic and functional characterization are needed to determine whether IL-10 rs1800896 contributes to interindividual variability in tacrolimus exposure and whether it may have potential applications in individualized immunosuppressive therapy. Full article

Treatment-resistant mental health conditions are common in primary care and challenging for clinicians. Trial-and-error prescribing can prolong morbidity and increase adverse drug reactions (ADRs). Pharmacogenomic (PGx) testing enables individualised prescribing by identifying gene–drug interactions affecting psychotropic response. Thirty adults with treatment-resistant mental health conditions underwent PGx testing using a commercial panel (one lost to follow-up [n = 29]). Patients received PGx-guided treatment (n = 8) or standard care (n = 21). Phenotypes were assigned per CPIC and DPWG guidelines, with prescribing guided by clinical experience where guidelines were unavailable. Medication histories were reviewed for gene–drug concordance, ADRs, and treatment failures. Clinical improvement at eight weeks was defined as “marked” or “moderate” improvement and/or ADR resolution. Actionable genotypes were common, particularly CYP2D6 (27.5% poor/intermediate drug metabolising phenotype) and CYP2C19 (37.9%). Guideline-actionable gene–drug interactions occurred in 37% of patients, and eleven patients possessed actionable phenotype at multiple loci. Gene–drug interactions were identified in nine patients and guidance was fully implemented in six. Clinical benefit at 8 weeks was achieved in 6/8 patients with genotype-guided changes versus 8/21 receiving standard care. PGx-guided prescribing may support improved antidepressant response and tolerability while reducing trial-and-error prescribing for treatment-resistant patients in primary care. Full article

Background: Although Short Read Next-Generation Sequencing (SR-NGS) is widely employed in diagnosis, its application in CYP21A2 genotyping remains limited due to its high sequence homology with its pseudogene, CYP21A1P. Herein, we present (a) a complete pipeline for the diagnostic use of SR-NGS in CYP21A2 genotyping following its assessment; (b) two distinct in-house bioinformatics pipelines for variant calling; and (c) the results by implementing this pipeline in diagnosis. Methods: A total of 221 subjects were studied, comprising a pilot group (n = 21), recruited for assessment of the assay, and a study group (n = 200) categorized in three subgroups, referred for CYP21A2 genotyping. Both groups underwent SR-NGS. Two different bioinformatics algorithms for variant calling were applied and variant filtration was performed using VarAFT (v2.17). In the study group, MLPA was additionally employed. Results: The SR-NGS assay, employing GATK HaplotypeCaller, demonstrated 100% sensitivity and specificity when compared to Sanger Sequencing; however, complex CYP21A2 rearrangements cannot be detected. In the study group, pathogenic variants were identified in 52.7%, 100% and 25% of cases in subgroups (a), (b) and (c) respectively, whereas gene duplications accounted for 12.3% (7/57) of subjects tested. Conclusions: This study provides a comprehensive protocol for the use of SR-NGS in a CYP21A2 diagnostic genotyping, integrating complementary bioinformatics pipelines and MLPA for copy number analysis. Full article

Pain is a leading cause of morbidity and healthcare utilization in sickle cell disease (SCD), and opioids remain central to treating vaso-occlusive and chronic pain. Yet opioid response varies widely, raising the question of whether pharmacogenetic testing should inform opioid prescribing. Our review examined the PubMed literature on pharmacogenomics and opioid efficacy in SCD. We focus on CYP2D6 as the clearest current pharmacogenetic signal for codeine and tramadol, and assess SCD-specific implementation studies, preemptive testing, and African pharmacoequity. The current evidence supports targeted CYP2D6-informed prescribing in selected contexts rather than universal testing for all opioids, while highlighting the need to integrate genotype with pain phenotype, drug–drug interactions, liver function, and clinically grounded implementation studies, and better characterize African and African-ancestry pharmacogene variation. Full article

Background: Personalized precision medicine adapts therapeutic strategies to individual characteristics. In psychiatry, suboptimal outcomes with antipsychotics are often related to adverse drug reactions, poor adherence and therapeutic failure. Pharmacogenetics, particularly CYP2D6 genotyping, can improve clinical outcomes through genotype-guided therapy. This study aimed to design and implement a pharmacogenomic and pharmacokinetic testing program for long-acting injectable (LAI) antipsychotics within the Galician Health Service to enhance personalized psychiatric care. Methods: The pilot program encompasses pharmacogenetic and pharmacokinetic testing. Inclusion criteria were broad, covering patients initiating or receiving LAI antipsychotic therapy, as well as those with prior adverse reactions in order to explore scenarios where pharmacogenetic and/or pharmacokinetic data could help with clinical decisions. Structured workflows, interdisciplinary training and integration of results into the electronic health record supported implementation. A pharmacogenetic panel was specifically designed for psychiatric care, targeting clinically relevant variants in CYP2D6, CYP3A4 and ABCB1. Results: A total of 540 patients were included, with primary testing reasons being clinical follow-up (54.6%) and oral-to-LAI transition (38.5%). The CYP2D6 phenotypes were 55% normal, 34% intermediate, 6.3% poor and 4.3% ultrarapid metabolizers. Atypical metabolism was observed in 6.7% of patients for CYP3A4 and in over half for ABCB1. Plasma drug levels were within the therapeutic range for most patients, though some measurements were above or below expected values. Conclusions: This pilot demonstrates a scalable, evidence-based approach to precision psychiatry for LAI antipsychotics, integrating pharmacogenetic and pharmacokinetic testing into routine care. The framework facilitates genotype-guided decision-making and supports broader adoption of pharmacogenomics in psychiatric practice. Full article

Cancer pain affects more than half of all oncology patients and represents one of the most challenging therapeutic problems in modern medicine. Despite the central role of opioids in cancer pain management—codified by the WHO analgesic ladder—the clinical response to these agents is highly variable between individuals. Pharmacogenomics promises to explain this heterogeneity by identifying functionally relevant genetic polymorphisms in genes encoding opioid receptors, metabolizing enzymes, and membrane transport proteins. However, after two decades of intensive research, clinical translation of genetic data into actionable prescribing strategies remains elusive. A narrative-critical review of the literature was conducted by searching PubMed, Scopus, and Web of Science databases from inception to March 2026, using the search terms “opioid,” “pharmacogenomics,” “pharmacogenetics,” “cancer pain,” “polymorphism,” and individual gene names (OPRM1, CYP2D6, COMT, ABCB1, SLC22A1, UGT2B7, and others). Reference lists of included articles were hand-searched for additional relevant studies. Inclusion was restricted to English-language articles reporting original data or systematic reviews on genetic polymorphisms and opioid response, with priority given to studies conducted in cancer pain populations. Clinical practice guidelines from CPIC, NCCN, ESMO, EAPC, and ASCO were consulted for current recommendations. This narrative-critical review examines the evidence on genetic polymorphisms relevant to opioid response in cancer pain, covering three functional categories: (1) pharmacodynamic genes, including opioid receptors (OPRM1, OPRD1, OPRK1) and neuromodulatory targets (COMT, KCNJ6, MC1R); (2) pharmacokinetic enzymes (CYP2D6, CYP3A4/5, UGT2B7); and (3) membrane transporters, including ABC efflux pumps (ABCB1, ABCG2, ABCC2) and SLC uptake carriers (SLC22A1, SLCO1B1, SLC6A4, SLC6A2). A dedicated section addresses the direct and indirect interference of the tumour itself—through the tumour microenvironment, neuroimmune signalling, epigenetic reprogramming, and cancer-induced organ dysfunction—on opioid pharmacogenomics. The overall evidence is poor and fragmented, a finding intrinsic to the extraordinary diversity, large number, and context-dependent biological activity of the polymorphisms identified. The tumour itself acts as a pervasive confounder that systematically distorts genotype–phenotype relationships. The path forward requires a paradigm shift from candidate-gene association studies to system pharmacogenomics and multi-omic integration. Full article

For over three decades, Proton Pump Inhibitors (PPIs) have served as the established primary therapy for acid-suppressive therapy; however, their clinical utility is frequently compromised by their slow onset of action, meal-time dependency, and metabolic variability driven by CYP2C19 polymorphisms. Potassium-competitive acid blockers (P-CABs) represent a definitive pharmacological shift, offering rapid, reversible, and genotype-independent inhibition of the H⁺/K⁺-ATPase. This review outlines the emergence of South Korea as a global epicenter for P-CAB innovation, predicated upon a strategic partnership between a high domestic burden of Helicobacter pylori infection and a rising incidence of refractory gastroesophageal reflux disease (GERD). We analyze the clinical and structural developments of indigenous Korean agents, specifically tegoprazan and fexuprazan, the latter of which features an optimized 9-h elimination half-life engineered to mitigate nocturnal acid breakthrough. A critical evaluation of recent clinical evidence is provided, including the most recent 2024 prospective Phase III data, which demonstrate that 14-day P-CAB-based triple therapy achieves significantly improved eradication rates in high-clarithromycin-resistance environments. Furthermore, we explore the emerging 2025 trend toward personalized, on-demand maintenance therapy and address critical long-term safety considerations, including the duration-dependent risk of metachronous gastric cancer identified in recent multicenter longitudinal studies. Ultimately, the South Korean clinical framework is providing the foundational evidence for a global transition toward P-CAB-centered treatment algorithms, redefining the standards of care in modern gastroenterology. Full article

Aim: To evaluate associations between polymorphisms in CYP3A4 (*1B, *22), CYP3A5 (*3), CYP2J2 (*7, rs11572325), ABCB1 (c.1236C>T, c.2677G>T/A, c.3435C>T, rs4148738) and ABCG2 (c.421C>A) and the occurrence of bleeding or occlusive events in patients receiving rivaroxaban in real-world clinical practice. Methods: A nested case-control study, divided into two substudies (bleeding and thromboembolic events), was conducted within a prospective cohort of 385 adults receiving rivaroxaban at University Hospital Centre Zagreb (September 2021–September 2024). Bleeding events were classified per ISTH criteria, and genotyping was performed using TaqMan real-time PCR. Cases and controls were balanced using entropy balancing, and associations were estimated with Bayesian logistic regression under a skeptical prior N(0, 0.355); LASSO regression was used to identify clinical and genetic predictors of outcomes. Results: In total, 71 patients (18.4%) experienced bleeding events, most frequently gastrointestinal (47.9%), while 314 patients served as controls. No pharmacogenomic variant showed a clear association with bleeding risk (raw and balanced odds ratios 0.80–1.35; 95% credible intervals crossing 1.0). LASSO regression identified age (OR 2.00 per decade), gastrointestinal comorbidity (OR 8.77), and eGFR as the dominant predictors of bleeding. Twenty-one patients experienced occlusive events (15 venous, 6 arterial); however, the low event count precluded meaningful pharmacogenomic analysis. Conclusions: Individual pharmacogenomic variants in CYP3A4, CYP3A5, CYP2J2, ABCB1, and ABCG2 together with pharmacogenetic-based phenotypes were not associated with clinically relevant bleeding in rivaroxaban-treated patients. Traditional clinical risk factors, particularly advanced age and gastrointestinal comorbidity, remain the dominant determinants of adverse outcomes. Routine pharmacogenomic testing to guide rivaroxaban dosing is not currently supported. Full article

Background: Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic tool used to predict how a drug moves through the body by incorporating real human physiology, including organ sizes, blood flows, tissue compositions, and enzyme activities. It has been widely employed to estimate drug exposure in different populations with organ impairment, genotype variabilities, and physiological variations. Metoclopramide is an antiemetic and prokinetic agent that is subject to CYP2D6 polymorphism. The study aims to develop PBPK models for several CYP2D6 variants to predict changes in the pharmacokinetic (PK) behavior of metoclopramide. Methods: To conduct this study, a literature review was conducted, and the retrieved physicochemical, biochemical, and PK data were integrated into PK-Sim to develop a PBPK model. Initially, a non-genotype-specific model was developed and extrapolated to genotype-based models. The models were verified using a Visual Predicted Check (VPC), mean predicted-to-observed ratio (R_pre/obs) values, and mean relative deviation (MRD). Results: The simulated profiles were aligned with the reported data, and all the predicted and observed PK parameters were comparable, as the R_pre/obs values were within the 0.5–2 range and MRD values were <2. Moreover, an increasing trend in AUC_0–∞ was observed across CYP2D6*wt/*wt, CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10, with approximately 1.63-, 2.64-, and 2.88-fold increases compared with the CYP2D6*wt/*wt genotype. Conclusions: The models have adequately estimated the PK behavior of metoclopramide across different CYP2D6 variants. These models might be helpful for populations with diverse CYP2D6 genotypes in dose optimization. Full article

Background: Vitamin D deficiency affects an estimated 40–60% of pregnant women worldwide and is associated with adverse obstetric and neonatal outcomes. Childhood asthma, the most prevalent chronic paediatric disease, has emerged as a plausible programming target, since vitamin D regulates foetal lung branching morphogenesis, calibrates the developing immune system, and modulates decidual and placental function in early gestation. Two landmark randomised trials, VDAART (intervention from weeks 10–18) and COPSAC2010 (from week 24), each reported a 20–25% reduction in offspring asthma or recurrent wheeze at age 3, yet neither reached significance in primary analysis, and the protective signal attenuated by school age. Post hoc stratification by baseline maternal 25-hydroxyvitamin D [25(OH)D] and 17q21 genotype recovered significant effects, raising the possibility that population-average nulls conceal a real but modifier-conditional benefit. Aim: This narrative review re-examines the evidence through a developmental-timing lens, arguing that the periconceptional and first-trimester window, rather than mid-gestation, is the biologically relevant interval for any protective effect. Methods: The review utilises a narrative synthesis of randomised trials, birth-cohort studies, mechanistic investigations, and recent meta-analyses (PubMed, Embase, Cochrane Library to April 2026) relevant to maternal vitamin D, placental biology, and offspring asthma. Findings: The periconceptional weeks coincide with implantation, decidualisation, the embryonic and pseudoglandular phases of airway morphogenesis, and the onset of epigenetic programming, while decidual CYP27B1 expression is prominent in the first trimester. Both trials initiated supplementation after branching morphogenesis was largely complete. Effect modifiers, including baseline 25(OH)D, vitamin D-binding protein, and maternal 17q21 genotype, indicate substantial inter-individual heterogeneity masked in unselected populations. Conclusions: Repositioning preventive supplementation toward the preconceptional and first-trimester window, stratified by baseline status, offers a biologically coherent strategy that existing mid-pregnancy trials have not tested. Adequately powered preconceptional trials with serial biomarker measurement and objective respiratory phenotyping are the priority. Full article

Pharmacogenetics (PGx) aims to optimize drug therapy by predicting medication response based on genetic variation in drug-metabolizing enzymes. However, observed drug metabolism may differ from genotype-predicted metabolizer status given external or acquired influences. This phenomenon is known as phenoconversion. As PGx testing becomes increasingly integrated into clinical care, understanding the contributing factors of phenoconversion is important for interpreting test results and guiding treatment. This scoping review aimed to categorize reported contributors of phenoconversion affecting CYP2D6, CYP2C19, and CYP3A4 metabolism. A structured literature search was conducted across Ovid MEDLINE^®, Embase Classic + Embase, EBM Reviews, and Clarivate Web of Science. Records were screened using predefined inclusion and exclusion criteria, and data were extracted from eligible studies describing factors associated with metabolic activity inconsistent with genotype-predicted phenotypes. From 6008 records identified, 43 studies met the inclusion criteria. Reported contributors clustered into pharmacological factors, including drug–drug and drug–drug–gene interactions, clinical factors such as inflammation, physiological and demographic factors including pregnancy and age-related changes, and environmental influences such as smoking. Pharmacological contributors were most frequently studied, whereas environmental and demographic influences were less well characterized. These findings highlight the multifactorial nature of phenoconversion and underscore the need for further investigations to support phenoconversion integration into PGx-informed clinical decision-making. Full article

Tacrolimus is an immunosuppressant drug commonly used in transplantation. Although multiple studies have demonstrated that polymorphisms in the CYP3A5 gene impact the metabolism of tacrolimus, routine pre-transplant testing for these markers is still not broadly implemented. TacroType™—a new laboratory-developed test implemented by One Lambda Laboratories—utilizes a qPCR-based six-plex assay for CYP3A5 genotyping and detects the three most common genetic variants (*3, *6 and *7) associated with loss of CYP3A5 protein function and reduced tacrolimus metabolism. TacroType was optimized to address known sources of protocol, technical or sample variability to achieve accurate and reproducible genotyping results. An analytical performance study was completed following CLSI guidelines. Accuracy was confirmed for each possible CYP3A5 genotype involving six target alleles using 32 well-characterized reference samples. TacroType exhibited accurate performance within a broad range of DNA concentrations and quality. Precision studies indicated consistent genotyping results across four operators, two instrument types and five lots of reagents. Accurate and reproducible assay performance was demonstrated using whole blood from 95 donors and buccal swabs from 65 donors. The analytical performance of TacroType was evaluated in 4014 total qPCR reactions, with a report rate of 99.8% and genotyping accuracy of 100% (95% confidence interval of 99.9%). Full article

Backgrounds/Objectives: Allele frequencies of genetic variants associated with complex diseases can contribute to varying degrees to predisposition depending on the population’s genetic profile. The aim of this study was to analyze the genetic diversity of 15 relevant SNVs that could modulate bone and cartilage metabolism in underrepresented structured populations. Methods: In a sample of 130 Mestizos and 304 natives from 8 native Mexican populations, SNVs related to multifactorial diseases were genotyped using a SNaPShot Multiplex kit and analyzed via capillary electrophoresis using an ABI PrismTM 3130 Genetic Analyzer (Applied Biosystems, Waltham, MA, USA.), and genetic profiles for 15 SNVs were obtained using GeneMapper software v. 3.2. Allele frequencies were calculated by locus and population using Power Stats and Arlequin v.3.1 software, for which the EM algorithm was used to compare reference populations obtained from the dbSNV database of the International HapMap project. Population structure, paired comparisons, and genetic differentiation between native, admixed, and reference populations (p value) were estimated through Fst tests using the STRUCTURE v.2.3.2 and Arlequin v.3.1 software. Results: Haplotype frequency combinations grouped as profiles showed higher predominance in the allelic combination A/A/G for rs9340799 (ESR1), rs700518 (CYP19A1), and rs1800795 (IL6) genes, respectively. Conclusions: Allelic profiles could be useful as medical tools for preventing and managing individuals or populations. Mexican populations showed high genetic variability among allelic risk profiles for estrogen control and response, as well as high frequencies of variant combinations associated with an increased inflammatory response, potentially resulting in high osteoclastogenesis. This analysis advances our understanding of the complexity of bone and cartilage metabolism in highly stratified populations. Full article