Methotrexate (MTX) treatment of juvenile idiopathic arthritis (JIA) is complicated by severe intolerance in approximately 30% of patients. MTX intolerance typically presents as nausea (anticipatory and postdose), vomiting, and behavioral symptoms. Although genetic variants in SLCO1B1 have been associated with MTX toxicity in retrospective studies of inflammatory bowel disease, prospective evaluation of this relationship in JIA patients is lacking. This study examined SLCO1B1-MTX intolerance associations accounting for clinical covariates in a prospective observational cohort of patients receiving standard weekly MTX doses (5-25 mg/m2). We performed a zero-inflated Poisson analysis using forward stepwise inclusion of clinical covariates followed by SLCO1B1 alleles. Among 217 JIA patients who completed the MTX Intolerance Severity Score (MISS) survey at 6 ± 2 months post-MTX initiation, the cohort was predominantly female (69.1%), White (76.5%), and received supplementation with folic acid (70.5%). Over 30% of patients met the threshold for MTX intolerance (MISS ≥ 6), and 62.7% of patients reported any MTX intolerance symptoms (MISS > 0). The SLCO1B1*37 allele was associated with lower odds of MISS > 0 (odds ratio = 0.60, P = 0.046) and a lower reported MISS score (incidence rate ratio = 0.74, P < 0.001) among individuals with non-zero intolerance, suggesting protection from MTX intolerance symptoms. These associations were consistent in sensitivity analyses stratified by folic acid supplementation. Further validation of these findings is needed to support future pharmacogenetic-guided MTX dosing strategies, including evaluation of other SLCO1B1 alleles.
OBJECTIVES:Clinical trial evidence is scarce for optimal antiplatelet strategies in patients undergoing intracranial artery stenting with CYP2C19 loss‑of‑function alleles, especially regarding the efficacy‑safety balance. METHODS:This single‑center retrospective study enrolled patients receiving genotype‑guided antiplatelet regimens for intracranial stenting between January and December 2023, with 6‑month follow‑up. Clinical outcomes were compared across CYP2C19 phenotypes. RESULTS:Among 205 patients, 46.8% were normal metabolizers, 40.5% intermediate metabolizers, and 12.7% poor metabolizers. Aspirin-clopidogrel was prescribed for all normal metabolizers, 80.7% intermediate metabolizers, and 19.2% poor metabolizers. No intergroup differences were observed in risks of ischemic stroke/transient ischemic attack (TIA), cardiovascular events, intracerebral hemorrhage (ICH), or any bleeding (all P > 0.05). In intermediate metabolizers and poor metabolizer subgroups, ischemic stroke/TIA rates were 11.1% in the aspirin-clopidogrel group and 9.68% in the aspirin-ticagrelor group, with no significant difference compared to normal metabolizers (4.17%). ICH rates were 1.39% in the aspirin-clopidogrel group and 6.45% in the aspirin-ticagrelor group, showing no significant difference versus normal metabolizers (1.04%). Multivariate logistic analysis found the number of stents (odds ratio [OR] = 2.70; 95% confidence interval [CI] = 0.89-6.95; P = 0.043) was a risk factor for ischemic stroke/TIA. Ticagrelor-based dual antiplatelet therapy (DAPT; OR = 10.57; 95% CI = 1.00-111.7; P = 0.05) and baseline l ow-density lipoprotein cholesterol (LDL-C; OR = 7.22; 95% CI = 1.80-29.01; P = 0.005) were associated with ICH risk. CONCLUSION:Antiplatelet regimens were adjusted for a subset of intermediate metabolizers and poor metabolizers prior to stenting, and the 6-month clinical outcomes were comparable across normal metabolizers, intermediate metabolizers, and poor metabolizers. The stent number was associated with ischemic stroke/TIA risk; baseline LDL-C and ticagrelor-based DAPT with ICH risk. These exploratory findings need validation in adequately powered studies.
BACKGROUND:Risperidone-clozapine response varies substantially in schizophrenia. HTR2A polymorphisms may influence antipsychotic response, but rs6311-rs6313 haplotypes remain unexplored in the Indonesian Batak population. This study evaluated associations of HTR2A rs6311-rs6313 with early risperidone-clozapine response. METHODS:This prospective observational case-control study included 160 Batak inpatients with schizophrenia, comprising 80 responders and 80 nonresponders to risperidone-clozapine therapy. Genetic analyses included Hardy-Weinberg equilibrium (HWE), minor allele frequency (MAF), linkage disequilibrium, genotype and allele association, haplotype, permutation testing, genetic models, and multivariable logistic regression. RESULTS:Genotype distributions conformed to HWE (P > 0.05), with both variants showing a MAF of 0.28 and strong linkage disequilibrium (r2 = 0.969, D' = 0.98). The rs6311 GG/rs6313 CC genotype was significantly associated with nonresponse to risperidone-clozapine therapy [odds ratio (OR) = 3.69, 95% confidence interval (CI): 1.10-12.36; P = 0.034], while the rs6311 G/rs6313 C allele was also associated with nonresponse (OR = 1.71, 95% CI: 1.04-2.80; P = 0.034). The recessive model remained significant after multivariable adjustment (adjusted OR = 3.36, 95% CI: 1.02-11.07; P = 0.046). TA and CG haplotypes remained significant after 10 000 permutations (P = 0.0415 and P = 0.0416), whereas single-marker associations lost significance (P = 0.0607). CONCLUSION:HTR2A variation was associated with early risperidone-clozapine response, with consistent signals under the recessive model and at the haplotype level. Haplotype associations remained significant after permutation correction, suggesting that haplotype analysis may provide a more robust approach for detecting pharmacogenetic contributions to treatment response.
Pre-emptive genotyping and genotype-guided dose adjustments are generally recommended for seven hypofunctional polymorphisms in the DPYD gene that are associated with fluoropyrimidine toxicity. However, targeted genotyping may miss uncommon and population-specific hypofunctional variants. Therefore, in 2021, we replaced conventional targeted genotyping with comprehensive DPYD exome sequencing. The objective of the current study was to identify uncommon hypofunctional variants and assess their association with fluoropyrimidine toxicity. In a cohort of 762 consecutive patients pre-emptively genotyped between 2021 and 2025, among the seven established risk variants, we identified *2A and HapB3 at their expected minor allele frequencies (MAF), but no carriers of any of the five other established risk variants. Interestingly, four patients were heterozygous for the rare missense c.257C>T variant (Pro86Leu; rs568132506), previously associated with fluoropyrimidine toxicity. The MAF (2.62 × 10-3) was similar to that previously described in Middle Eastern populations but 26-fold higher than in the gnomAD global population. Three of the carriers (75%) developed grade 3-4 fluoropyrimidine toxicity after one or two cycles, corresponding to a relative risk of 14.5 (95% confidence interval: 5.0-30.4, P = 0.0009) compared with a control cohort without hypofunctional DPYD variants. Our findings add to the growing body of evidence indicating that DPYD c.257C>T may be associated with severe fluoropyrimidine toxicity. Future studies should examine the clinical utility of including uncommon but potentially actionable variants, such as c.257C>T, into pre-emptive genotyping algorithms. This may be particularly important in multiethnic populations in which these variants can be more prevalent than those variants for which pre-emptive genotyping is generally recommended.
Associations between genetically predicted activity of metabolic enzymes and risks of adverse events from tyrosine kinase inhibitors (TKIs) may inform dosing to optimize treatment outcomes in patients with cancer. The goal of this study is to investigate the associations between UGT1A1, CYP3A4, and CYP1A2 activity and toxicity from nilotinib and pazopanib treatment. A retrospective pharmacogenetic association study was conducted in 117 participants of the Michigan Genomics Initiative who received pazopanib (n = 103) or nilotinib (n = 14). Clinical information, including patients' disease, treatment, and toxicity was collected via retrospective review of medical records. No associations were found between the genetically predicted activity of any of the three enzymes and the composite endpoint of severe toxicity or treatment modifications because of toxicity. In the secondary hypothesis-generating analyses, patients with reduced UGT1A1 activity had an increased incidence of increased aspartate aminotransferase/alanine aminotransferase (44 vs. 25%; P = 0.034) and hypertension (52 vs. 31%; P = 0.024). In addition, patients with increased CYP1A2 activity from carrying CYP1A2*1F had a lower incidence of severe toxicity from pazopanib (β-coefficient = -0.163, 95% confidence interval: -0.19 to -0.14, P = 0.008). Future investigations are needed to confirm these associations and determine whether personalized TKI treatment can optimize therapeutic outcomes in patients with cancer.
OBJECTIVE:This study analyzed the correlation and differences between the gene polymorphisms of ATP-binding cassette B1 (ABCB1), which encode the efflux drug transporter P-glycoprotein, and the efficacy and plasma concentration of perampanel (PER) in patients with refractory epilepsy. METHODS:Plasma samples were collected from 115 patients with epilepsy who received PER treatment for at least 21 days. The ABCB1 genotypes were detected using first-generation Sanger sequencing, and the PER plasma concentration was measured using ultra-high performance liquid chromatography-mass spectrometry. RESULTS:The overall efficacy of PER in treating patients with refractory epilepsy was observed in 64.3% of patients. The ABCB1 rs2032582 gene polymorphisms were significantly associated with the therapeutic efficacy of PER in refractory epilepsy. When compared with patients with the wild-type homozygous genotype, the plasma concentrations of PER were significantly higher for patients with the P-glycoprotein-encoding ABCB1 rs2032582 and ABCB1 rs1045642 mutant genotypes (P < 0.05). When the plasma concentration of PER exceeded 305 ng/ml, patients more effectively responded to PER treatment (area under the curve: 0.614, P < 0.05). CONCLUSION:ABCB1 gene polymorphisms are important predictors of effective with PER treatment and serve as factors that affect the achievement of therapeutic plasma concentrations of PER, and they have contrasting effects.
BACKGROUND:As precision medicine advances, integrating pharmacogenomics (PGx) into routine practice requires coordinated efforts among healthcare professionals. This study evaluated the knowledge, attitudes, and perceptions of Pakistani physicians, nurses, and pharmacists toward PGx implementation. METHODS:This cross-sectional, prospective, web-based study was carried out employing a self-administered questionnaire involving 1560 respondents across Pakistan. RESULTS:The respondents comprised 70% males. Most respondents (95%) were in the age range of 20-40 years, and the majority held a bachelor's degree (94%). Pharmacists comprised the largest group (64%), followed by physicians (24%) and nurses (12%). Participants responded from academia (33%), healthcare settings (46%), industry (14%), and regulatory authorities (6.5%). Most (89%) lack exposure to PGx, and only 10% had PGx training. Sixty-one percent had under 5 years of experience. Only 12.8% demonstrated good knowledge, yet positive attitudes (66.6%) and perceptions (67%) predominated. Knowledge was not associated with attitude or perception but was significantly linked with training and experience. Training and experience were significantly tied to positive perceptions, with years of experience showing more consistent associations across domains. CONCLUSION:While Pakistani healthcare professionals hold positive attitudes toward PGx, baseline knowledge remains low. Training and experience are key drivers of readiness. There is an urgent need for structured training, professional workshops, and curriculum integration to support PGx adoption in Pakistan.
OBJECTIVES:We examined the distribution of clinically-relevant DPYD polymorphisms in Yanomami and Munduruku individuals, from Indigenous reservation areas in the Brazilian Amazon. The estimated proportion of Native ancestry exceeded 90% in all participants. METHODS:Eight DPYD single nucleotide variants (SNVs), including rs3918290, rs55886062, rs67376798, and rs75017182, widely recognized for their established associations with fluoropyrimidine-induced toxicity, plus rs115232898, rs2297595, rs1801265, and rs4294451 were genotyped, using Taqman probes. The distribution of haplotypes comprising rs1801265, rs2297595, and rs75017182 was assessed. RESULTS:Six variants, namely rs3918290, rs55886062, rs67376798, rs75017182, rs115232898, and rs2297595, were absent in the Yanomami and Munduruku cohorts. In striking contrast, rs1801265 and rs4294451 were common, with minor allele frequency (MAF) ranging between 0.41 (Yanomami) and 0.47 (Munduruku); these SNVs were in perfect (Yanomami) or strong (Munduruku) linkage disequilibrium. Regarding haplotypes comprising rs1801265, rs2297595, and rs75017182, only two were observed: one with the three reference alleles (T-A-C) and the other (C-A-C) with the variant rs1801265 C allele (frequency 41% in Yanomami and 47% in Munduruku). CONCLUSION:The variants prioritized in the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, namely rs3918290, rs55886062, rs67376798, and rs75017182 were not detected in the Munduruku and Yanomami cohorts. Thus, pharmacogenetic screening of such variants would not provide reliable pharmacogenetic-guided recommendations for fluoropyrimidine dosing in the enrolled Native groups, and possibly other Amerindian ethnicities and admixed Latin American populations with major Native ancestry. DPYD SNVs rs1801265 and rs4294451 were quite common (MAF = 0.41-0.47) and in perfect or nearly complete linkage disequilibrium, which might result in reduced risk of fluoropyrimidine-induced toxicity.
Major depressive disorder (MDD) is a multifactorial psychiatric disorder increasingly associated with immune-inflammatory mechanisms. Pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), have been implicated in the pathophysiology of MDD through their influence on neuroinflammation, neurotransmitter regulation, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. This systematic review aimed to evaluate the association between TNF-α and IL-1β gene polymorphisms and susceptibility to MDD, treatment response, and related clinical outcomes. A systematic literature search was conducted in PubMed, Embase, and ScienceDirect databases from inception to March 2026, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating TNF-α and IL-1β gene polymorphisms in clinically diagnosed MDD patients were included. Case-control studies published in English involving adult human participants were considered eligible. Data regarding study design, population, polymorphisms, and clinical outcomes were extracted and qualitatively synthesized. A total of 172 records were identified, of which nine studies met the inclusion criteria. Included studies primarily investigated TNF-α rs1800629 and IL-1β rs16944 polymorphisms across diverse populations. Several studies reported significant associations between these polymorphisms and increased susceptibility to MDD, suicide risk, severity of depressive symptoms, age of onset, and antidepressant treatment response. However, some studies reported no statistically significant associations, indicating heterogeneity across ethnic groups and study populations. Variability in age, medication status, and environmental stressors may have contributed to inconsistent findings. The findings of this systematic review support the involvement of inflammatory cytokine gene polymorphisms in the pathophysiology of MDD, particularly TNF-α and IL-1β variants. These polymorphisms may contribute to depression susceptibility and treatment response through immune-inflammatory mechanisms. Further large-scale, ethnically diverse studies incorporating gene-environment interactions and next-generation sequencing approaches are needed to validate cytokine-related genetic biomarkers in MDD.
Drug-induced QT prolongation (diQTP) can lead to rare, but potentially fatal adverse effects of many medications, yet individual susceptibility varies due to both clinical and genetic factors. SDHAF3 p.F53L (rs62624461) is a genetic variant that plays a role in mitochondrial function and was previously associated with diQTP in one small prior study. Therefore, the objective of this retrospective pharmacogenetic study was to evaluate whether SDHAF3 p.F53L is associated with clinically significant diQTP. Data were obtained from the Michigan Genomics Initiative, which links genotype information with electronic health records at Michigan Medicine. Adult patients with available genotype and electrocardiogram data who received at least one high-risk QT-prolonging drug between 2001 and 2022 were included. The analysis was limited to 5848 patients of European ancestry, of whom 320 (5.5%) were carriers of the SDHAF3 p.F53L variant. QT prolongation was defined as a QTc greater than or equal to 500 ms or an increase greater than 60 ms from baseline during high-risk QT-prolonging drug prescription. Logistic regression under a dominant genetic model assessed associations between variant carrier status and diQTP, with and without propensity score adjustment. Baseline demographics and comorbidities were similar between carriers and noncarriers. No significant association was observed between SDHAF3 p.F53L and diQTP [unadjusted odds ratio (OR) = 1.06, 95% confidence interval (CI) = 0.76-1.48, P = 0.742; adjusted OR = 1.05, 95% CI = 0.74-1.51, P = 0.773]. These results suggest that SDHAF3 p.F53L does not meaningfully influence diQTP risk in a large, real-world clinical cohort. Future studies should examine this variant across diverse populations.
INTRODUCTION:Vincristine is limited by its adverse effect of peripheral neuropathy with only a few inconclusive reports of its genetic occurrence. Therefore, the present research work was intended to identify the distribution of rs1045642 polymorphism in ABCB1 gene and rs924607 polymorphism in CEP72 gene, and their association with clinically documented neurological adverse drug reactions to vincristine. METHODS:Seventy-five children below 18 years diagnosed with acute lymphoblastic leukemia receiving vincristine were followed for 6 months and analyzed for correlation with vincristine-associated neuropathy. RESULTS:Twenty of 75 patients were homozygous for the risk allele (TT at rs924607) of CEP72 genotype and 25 of 75 patients were homozygous for the risk allele (TT at rs1045642) of ABCB1 genotype. Among patients with the high-risk ABCB1 genotype (TT at rs1045642), 13 of 25 (52%) developed at least one episode of grade 1-3 neuropathy, and had a statistically significant 4.3 times risk of developing neurotoxicity in comparison to patients with the ABCB1 CC or CT genotypes [10 of 50 (20%) patients, odds ratio: 4.3, 95% confidence interval: 1.5-12.3; P = 0.0060]. The patients receiving average dose of vincristine of greater than or equal to 2 mg/m2 (58.3%) when compared to those receiving an average dose of less than 2 mg/m2 (25.4%) had 4.1 times risk of developing neurotoxicity (odds ratio: 4.1, 95% confidence interval: 1.1-14.8; P = 0.0304). CONCLUSION:This study emphasizes the significant association of ABCB1 genotype (TT at rs1045642) with vincristine-associated neuropathy and highlights the relevance of higher average doses of vincristine in causing neurotoxicity.
BACKGROUND:P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette (ABC) transporter, is expressed in the apical membrane of syncytiotrophoblast cells and plays a crucial role in placental drug transport. However, the roles of the vitamin D receptor (VDR) and steroid receptor coactivators (SRCs) family members in VDR-mediated transcriptional regulation of the ABCB1 gene in response to 1,25-dihydroxyvitamin D3 in the placenta remain unclear. METHODS:VDR-mediated drug efflux was first examined using VDR-deficient mice. Subsequently, the roles of VDR and SRCs in regulating placental P-gp were investigated via specific deletion of VDR and SRCs in mouse trophoblast cells in vivo, and further validated using transfection assays in placental trophoblast cells in vitro. Additionally, the mechanisms underlying VDR-regulated ABCB1 expression were explored. RESULTS:In this study, we first knocked out the Vdr gene in C57BL/6J mice and observed a significant downregulation of P-gp in the placenta. Furthermore, both gain-of-function and loss-of-function assays demonstrated that VDR promotes P-gp expression in human trophoblast cells. Mechanistically, VDR induces ABCB1 gene transcription by binding to the region 2026-2031 bp upstream of the transcriptional start site in the ABCB1 gene promoter in human trophoblast cells. Moreover, we found that SRCs interact with VDR in trophoblast cell lines, and both in vivo and in vitro studies showed that SRC-1 enhances placental ABCB1 expression. Further investigations confirmed that SRC-1 is an essential transcriptional coactivator for VDR-mediated ABCB1 transactivation in human trophoblast cells. CONCLUSIONS:Our findings reveal a novel mechanism regulating placental P-gp expression, which may assist clinicians in ensuring the safety of drug therapy during pregnancy.
OBJECTIVE:Glucocorticoids (GCs) are essential for the therapy of acute lymphoblastic leukemia (ALL), but glucocorticoid resistance remains a major clinical challenge, and its molecular mechanisms are not fully understood. This study aimed to investigate the role of ZFP36L2, an RNA-binding protein and potential driver gene in T-ALL, in regulating glucocorticoid sensitivity in ALL. METHODS:ZFP36L2 expression in ALL were reanalyzed from RNA sequencing data, and the correlation between ZFP36L2 expression and clinical outcomes in ALL patients was analyzed. ZFP36L2 was knocked down in T-ALL cells to observe its effects on glucocorticoid resistance and related signaling pathways. The effect of GCs combined with γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or MEK inhibitor trametinib on drug sensitivity was detected in vitro . RESULTS:ZFP36L2 expression was significantly lower in T-ALL than in B-ALL, and low ZFP36L2 expression was associated with poor early disease responses and higher relapse risk in ALL. ZFP36L2 knockdown in T-ALL cell lines significantly increased glucocorticoid resistance, weakened glucocorticoid receptor upregulation, impaired apoptosis, reduced Bcl-2 interacting mediator of cell death induction, and repressed BCL2 downregulation. Moreover, ZFP36L2 was critical for glucocorticoid-mediated suppression of the NOTCH1-HES1 and mitogen-activated protein kinase pathway. Notably, combined treatment with GCs and DAPT or trametinib enhanced drug sensitivity in vitro . Mechanistically, ZFP36L2 directly binds to the UAUUUAUU motifs in the 3' untranslated regions of BCL2, Bcl-2 interacting mediator of cell death, and NOTCH1 mRNAs, thereby regulating their stability. CONCLUSION:These findings demonstrate that ZFP36L2 is a potential regulator of glucocorticoid responsiveness in T-ALL. Combining GCs with DAPT or trametinib offers a potential therapeutic strategy for T-ALL patients, especially those with ZFP36L2 mutations or low ZFP36L2 expression.
OBJECTIVES:This study compared psychiatrist and primary care practitioner (PCP) perspectives on pharmacogenomics and barriers to its use in guiding antidepressant prescribing. METHODS:Psychiatrists and PCPs across the USA were invited to complete an anonymous 31-item online survey that collected demographic information, knowledge and experience with pharmacogenomics, and attitudes and perspectives on the clinical use of pharmacogenomics. RESULTS:Psychiatrists ( n = 36) reported greater familiarity and experience with antidepressant pharmacogenomics than PCPs ( n = 11); however, both lacked familiarity with implementing pharmacogenomic testing and related clinical resources. Identified barriers to testing among psychiatrists focused predominantly on concerns over clinical utility and applicability to patients. The reported barriers among PCPs were lack of test information and lack of knowledge on how to order and how to utilize pharmacogenomic results. However, all respondents supported multigene panel-based pharmacogenomic testing and including all potentially impacted medications in test reports. CONCLUSION:Despite a low overall response rate and disproportionate survey participation between provider types, this study identified knowledge and experience as current barriers for psychiatrists and PCPs to implement pharmacogenomic-guided antidepressant prescribing. Importantly, both clinician groups indicated interest in pharmacogenomics education, professional support for implementation, and panel-based pharmacogenomic testing with comprehensive medication management reporting.
OBJECTIVES:Gastroesophageal reflux disease is primarily treated with proton pump inhibitors (PPIs), which are metabolized by cytochrome P450 2C19 ( CYP2C19 ) in the liver. CYP2C19 polymorphisms affect PPI plasma levels, with rapid (2-27%) and ultra-rapid (<1-5%) metabolizers needing higher doses, while poor (3-15%) and intermediate (27-47%) metabolizers require lower doses for therapeutic effectiveness. Antireflux surgery is recommended for patients refractory to medical therapy or with symptomatic hiatal hernias. METHODS:This is a multisite retrospective review of adult patients from 2012 to 2023 diagnosed with gastroesophageal reflux disease who underwent hiatal hernia operations and completed CYP2C19 testing. CYP2C19 phenotypes were grouped as poor metabolizer/intermediate metabolizer, normal metabolizers, or rapid metabolizer/ultra-rapid metabolizer. Hiatal hernia size was classified as small, medium, or large based on preoperative and intra-operative findings. Descriptive statistics were used. RESULTS:Eighty patients [female: 66%, median age: 60.5 (interquartile range 53.3-67.0) years, 90% White, 6% Hispanic] had CYP2C19 testing and underwent a hiatal hernia repair. CYP2C19 phenotypes were poor metabolizer (4%), intermediate metabolizer (24%), normal metabolizers (30%), rapid metabolizer (31%), and ultra-rapid metabolizer (11%). About 28% were grouped as poor metabolizer/intermediate metabolizer and 43% as rapid metabolizer/ultra-rapid metabolizer. Among patients with small ( n = 41) and medium ( n = 23) hernias, 39% and 57%, respectively, were classified as rapid metabolizer/ultra-rapid metabolizer, suggesting they were resistant to PPIs. CONCLUSION:The prevalence of rapid metabolizer/ultra-rapid metabolizer CYP2C19 phenotypes in patients undergoing antireflux surgery is higher than generally reported in the general population. These patients could potentially benefit from higher PPI doses or surgical intervention if ineffective. Prospective multisite studies with diverse, representative samples are needed to confirm these findings.
AIM:This study aimed to evaluate the impact of CYP3A5 gene polymorphism on the pharmacokinetics, therapeutic efficacy, and safety of tacrolimus in pediatric patients with Henoch-Schönlein purpura nephritis (HSPN). METHODS:This study used a retrospective observational design to investigate pediatric patients with HSPN treated with tacrolimus. The polymorphism at the CYP3A5 was detected using PCR technology. The concentration of tacrolimus was quantitatively determined by ultra-performance liquid chromatography. The study systematically analyzed the impact of CYP3A5 gene polymorphism on the pharmacokinetic parameters of tacrolimus (including trough concentration C0, dose D, and dose-corrected concentration C0/D), clinical efficacy, and adverse reactions. RESULTS:The study enrolled 103 pediatric patients. Comparative analysis revealed that patients with CYP3A5*1/*1 or *1/*3 genotypes exhibited significantly lower tacrolimus C0 and C0/D at various time points when compared with CYP3A5*3/*3 genotype carriers. Furthermore, CYP3A5*1 expressers (CYP3A5*1/*1 and *1/*3) demonstrated markedly reduced tacrolimus C0 and C0/D levels across multiple time points relative to CYP3A5*3 nonexpressers (CYP3A5*3/*3). However, CYP3A5 genetic polymorphisms did not demonstrate significant associations with clinical efficacy or adverse reactions. CONCLUSION:The polymorphism of the CYP3A5 gene may provide information on the pharmacokinetics of tacrolimus in pediatric with HSPN, but its clinical relevance has not yet been demonstrated.
OBJECTIVE:To investigate the association between CFTR genotypes and clinical and nutritional outcomes in children and adolescents with cystic fibrosis (CF) receiving care within the public health system of Espírito Santo, Brazil. METHODS:This cross-sectional study retrospectively analyzed clinical and genetic data from 110 individuals under 18 years with confirmed CF, followed at a state reference center between 2007 and 2024. CFTR variants were classified by functional consequence and grouped by severity. Outcomes included pancreatic insufficiency, forced expiratory volume in 1 s (FEV1%), Shwachman-Kulczycki score, nutritional status, and chronic airway colonization by Pseudomonas aeruginosa . Associations were assessed using appropriate statistical tests. RESULTS:A high degree of CFTR genotypic heterogeneity was observed, with predominance of the F508del variant (72.7%) alongside a substantial proportion of non-F508del and rare pathogenic variants. Individuals carrying two class I-III variants had a higher frequency of pancreatic insufficiency ( P = 0.026). The presence of p.Phe508del was associated with worse pulmonary function ( P = 0.031) and bone demineralization ( P = 0.026). The Shwachman-Kulczycki score correlated negatively with age and age at diagnosis and positively with BMI z -score and FEV1%. No significant associations were found between genotype and chronic P. aeruginosa colonization, liver disease, or overall disease severity. CONCLUSION:CFTR genotypic heterogeneity was high, with minimal function variants associated with poorer clinical outcomes. The notable presence of rare variants underscores the need for regional studies to better characterize phenotypic variability and support precision medicine strategies in middle-income settings.
While prior studies have focused on the clinical utility of pharmacogenetic (PGx) testing, less is known about factors that influence physicians' continued use of PGx testing in routine practice. Using data from the PGx-SParK trial, we examined whether the actionability of PGx test results from a physician's initial referral predicted subsequent PGx referral behavior. Youth aged 6-24 years referred for PGx testing in Western Canada between October 2020 and November 2025 were included. For each physician, an index PGx referral was identified and linked to patient characteristics, testing turnaround time, and CYP2B6, CYP2C19, and CYP2D6 results. Actionability for psychotropic prescribing was defined based on current PGx guidelines and categorized as current, future, or none. The number of subsequent referrals per physician was modeled using generalized linear models with a Poisson distribution corrected for overdispersion and adjusted for follow-up time and relevant covariates. Among 371 physician index referrals, 90% of tested youth had at least one current (22%) or future (68%) actionable result. Over a mean follow-up of 29 months, 52% of physicians made at least one subsequent PGx referral. Neither current nor future actionability of the initial PGx test results was associated with subsequent referral behavior. However, patient age (older) and physician speciality (psychiatrists) were associated with greater odds of a subsequent referral. These findings suggest that sustained physician engagement with PGx testing in youth mental healthcare may be driven more by implementation context and physician-level factors than by the clinical actionability of test results.
PURPOSE:Valsartan, an angiotensin II receptor blocker, is widely used for hypertension and heart failure. While its cardiovascular benefits are established, its broader pharmacological effects remain incompletely characterized. This study aimed to identify genetic variants associated with valsartan use and to systematically explore its potential effects and adverse events across a wide range of phenotypes. METHODS:Using UK Biobank data, we selected participants of European ancestry prescribed valsartan as cases, compared with controls not prescribed any ARBs. A genome-wide association study (GWAS) was conducted to identify suggestive genetic variants associated with valsartan use. These variants were then used as instruments in a phenome-wide association study (PheWAS) to screen for associated traits. Mendelian randomization analyses, including inverse-variance weighted and pleiotropy-robust methods, were employed to assess potential causal relationships. RESULTS:The GWAS identified 19 suggestive single nucleotide polymorphisms ( P < 1 × 10 -5 ) near genes, including PREP , GCLC , and ZNF133 . The PheWAS analysis revealed associations with 14 phenotypes, including lower levels of total cholesterol ( β = -0.59) and low-density lipoprotein cholesterol (LDL-C) ( β = -0.56), and increased risk of cough (odds ratio = 1.67). Mendelian randomization provided genetic evidence consistent with potential causal effects of valsartan in lowering LDL-C ( β = -2.34 × 10 -3 ) and reducing the risk of transient cerebral ischemic attack. CONCLUSION:Our genetic-based study suggests valsartan use may be associated with lowered LDL-C and reduced risks of certain ischemic cardiovascular events. These findings generate novel hypotheses regarding the drug's pleiotropic effects and potential applications beyond hypertension management, which warrant further clinical investigation.
