JAMA Netw Open. 2025 Aug 1;8(8):e2526714. doi: 10.1001/jamanetworkopen.2025.26714.

NO ABSTRACT

PMID:40779270 | DOI:10.1001/jamanetworkopen.2025.26714

Pediatr Pulmonol. 2025 Aug;60(8):e71229. doi: 10.1002/ppul.71229.

ABSTRACT

Cystic fibrosis (CF) was once a fatal disease of childhood, but with advances in combination CFTR modulator therapies, life expectancy for persons with CF (PwCF) has increased. Despite remarkable improvements in life expectancy, CF is a chronic multiple organ system disease and comorbidities characterized by recurrent respiratory infections, pancreatic insufficiency, diabetes, liver disease, depression, anxiety, and bone disease resulting in exposure to many drugs. The Clinical Pharmacogenetics (PGx) Implementation Consortium (CPIC) publishes evidence-based guidelines for use of PGx to guide dosing for drug-gene interactions. This study aimed to assess the current use of PGx testing in CF care at CF Foundation-accredited care centers and affiliate programs (CFF-ACCAP) across the United States. A 14-item survey was distributed electronically to CF Foundation-accredited care centers and affiliate programs in the United States using the CF Foundation email exchange. Overall, 74 responses were received from a potential of the 287 CFF-ACCAP. Since each individual CFF-ACCAP may have had multiple team members who could have received and responded to the survey, it is possible that these responses include multiple respondents from a single center. Only eight (4%) respondents affirmed they were obtaining PGx testing beyond cystic fibrosis transmembrane conductance regulator (CFTR) and 66 (89%) respondents answered that they were not currently doing PGx for drug-gene pairs beyond CFTR. Based on this landscape survey, PGx is not commonly implemented in US CFF-ACCAP, but providers are open to using PGx to improve care in PwCF. Several barriers limit the implementation of PGx in CFF-ACCAP, which calls for guidance on how to effectively integrate PGx into CF clinical care.

PMID:40778643 | DOI:10.1002/ppul.71229

Pharmacotherapy. 2025 Aug 8. doi: 10.1002/phar.70048. Online ahead of print.

ABSTRACT

Succinylcholine, a commonly used neuromuscular blocker, is hydrolyzed by the pseudocholinesterase (also known as butyrylcholinesterase) enzyme in the plasma to inactive metabolites. Individuals who have inherited genetic variants in the BCHE gene that result in decreased or no pseudocholinesterase enzyme activity are at increased risk of prolonged neuromuscular blockade with succinylcholine. Although succinylcholine/BCHE is one of the earliest identified pharmacogenomic drug/gene associations, clinical implementation remains the exception rather than the norm today. This review will explore the historical roots of pseudocholinesterase deficiency, its therapeutic implications for succinylcholine use, and future considerations for BCHE genetic testing to minimize the occurrence of prolonged neuromuscular blockade that can cause serious physical (i.e., apnea) and psychological (i.e., post-traumatic stress) consequences for patients. A summary and critical examination of the published literature that includes BCHE genetic testing in relation to succinylcholine response is also provided. Prolonged paralysis with succinylcholine may be prevented with preemptive BCHE genetic testing.

PMID:40778538 | DOI:10.1002/phar.70048

Stud Health Technol Inform. 2025 Aug 7;329:1594-1595. doi: 10.3233/SHTI251118.

ABSTRACT

Pharmacogenomics (PGx) has the potential to improve prescribing practices. In 2012, our institution developed a multidisciplinary program to implement PGx-CDS to support the clinical practice. CDS has been implemented for 45 drug-gene interactions, in 42,000 patients with PGx tests results, and in 2023, approximately 9281 CDS interventions have triggered at the time of prescribing. The program has been successful.

PMID:40776135 | DOI:10.3233/SHTI251118

Stud Health Technol Inform. 2025 Aug 7;329:1079-1083. doi: 10.3233/SHTI251005.

ABSTRACT

Pharmacogenomics (PGx) is pivotal in personalized medicine, particularly in cancer care, where drug efficacy and toxicity often vary with genetic variability. This study investigates the prevalence of CYP2D6-related medications and phenotypes in a cohort of 5,576 female breast cancer patients using genomic and electronic health record (EHR) data from the NIH's All of Us Research Program. A total of 77% of patients were prescribed at least one CYP2D6 metabolized drug. A customized pipeline was developed to determine CYP2D6 genotypes and phenotypes, identifying actionable phenotypes in 12.5% of patients. The prevalence of CYP2D6-associated drugs, including Tamoxifen, ondansetron, and tramadol, were widely prescribed and increased significantly following cancer diagnosis. Approximately 25% of phenotyped patients exhibited non-normal metabolizer types, emphasizing the importance of pharmacogenomic considerations in clinical decision-making. These findings emphasize the potential of incorporating PGx guidelines into routine clinical practice to optimize breast cancer treatment and improve patient outcomes.

PMID:40776023 | DOI:10.3233/SHTI251005

J Orthop Surg Res. 2025 Aug 7;20(1):742. doi: 10.1186/s13018-025-06171-7.

ABSTRACT

The limited understanding of the prognostic implications of immune checkpoint molecules in osteosarcoma (OS) poses significant challenges for improving patient outcomes. There is a gap in the identification of reliable biomarkers that can predict treatment response and prognosis in OS patients. This study focused on investigating the prognostic value of immune checkpoints, specifically BTN3A1, SIRPA, and TDO2, using data from the TARGET database and clinical follow-up data from our hospitals. By conducting univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses, we identified these immune checkpoints as significant prognostic indicators. A three-immune-checkpoint genetic prognostic risk model was developed, which demonstrated different prognostic implications across different clinical subgroups. Drug sensitivity analysis revealed that BTN3A1, SIRPA, and TDO2 were correlated with the efficacy of several antineoplastic agents, including hydroxyurea and docetaxel. Validation in our clinical cohort highlighted the significant prognostic value of SIRPA, suggesting its potential as a target for immunotherapy. These findings established a framework for using immune checkpoints as prognostic biomarkers, highlighting their important role in enhancing personalized treatment strategies for OS patients.

PMID:40775344 | DOI:10.1186/s13018-025-06171-7

J Transl Med. 2025 Aug 7;23(1):884. doi: 10.1186/s12967-025-06720-y.

ABSTRACT

Metformin, a widely prescribed treatment for type 2 diabetes mellitus (T2DM), demonstrates significant inter-individual variability in its therapeutic response. This variability is potentially driven by genetic differences in drug transporters. Among these transporters, the organic cation transporter 2 (OCT2) plays a critical role in the pharmacokinetics of metformin by mediating its uptake into renal epithelial cells for excretion. This review explores the potential impact of genetic variations in OCT2 gene (SLC22A2) on the pharmacokinetics and pharmacodynamics of metformin. These genetic variations can alter metformin accumulation in the kidneys, impacting its overall clearance and therapeutic effectiveness. Furthermore, the interactions of metformin with other drugs, especially in T2DM patients, can compromise its pharmacokinetics. Thus, it is important to consider the influence of genetic variability and potential drug interactions when prescribing metformin. Incorporating genetic testing into clinical decision-making could help optimize dosing strategies and improve treatment outcomes, particularly when managing patients with complex comorbid conditions.

PMID:40775340 | DOI:10.1186/s12967-025-06720-y

Drug Metab Dispos. 2025 Jul 7;53(8):100119. doi: 10.1016/j.dmd.2025.100119. Online ahead of print.

ABSTRACT

Thiopurine-induced leucopenia (TIL) affects more than 20% of Asians despite dose optimization via NUDT15 and TPMT genotyping. Elevated levels of DNA-thioguanine nucleotide (DNA-TG) have been implicated in the development of TIL. This study aimed to identify genetic polymorphisms influencing TIL through the DNA-TG metabolic pathway and construct a predictive model in Chinese inflammatory bowel disease patients. A prospective cohort of inflammatory bowel disease patients receiving thiopurines from December 2018 to December 2019 was analyzed. A total of 294 single-nucleotide polymorphisms across 29 genes were screened using the MassARRAY system. Candidate single-nucleotide polymorphisms associated with DNA-TG exposure or TIL (P < .1) were selected for validation. Independent risk factors were identified through multivariate logistic regression and incorporated into a predictive nomogram. Thiopurine metabolites, including DNA-TG and 6TGN, were quantified. DNA-TG, but not 6TGN, exposure was significantly associated with TIL (P = 8.3 × 10-7, P = .41). Sex, along with variants in NUDT15 (rs116855232 c.415C > T), TPMT (rs9465102), MOCOS (rs73430958), and RRM1 (rs1735053), were identified as independent predictors of TIL. The resulting nomogram demonstrated good discriminative performance (area under the curve = 0.72, 95% confidence interval: 0.65-0.78). Individuals stratified into low-, medium-, and high-risk groups based on total point thresholds (25.0 and 196.8), showed significant differences in TIL incidence in both NUDT15 variants and nonvariants (P = 1.8×10-5, P = .045). Our findings indicate that in addition to NUDT15, novel genetic variants in TPMT, MOCOS, and RRM1 are potential predictive markers of TIL. The new nomogram enables more accurate identification of individuals at high risk of TIL, allowing for the proactive adjustment of thiopurine therapy. SIGNIFICANCE STATEMENT: Compared with prior studies limited to NUDT15 and TPMT variants, it was the first pharmacogenomic study to investigate genetic polymorphisms affecting thiopurine-induced leucopenia (TIL) and DNA-thioguanine nucleotide metabolism, constructing a clinically actionable TIL prediction model. We identified novel associations of TPMT, MOCOS, and RRM1 variants with TIL risk, offering key insights for precision dosing in Asian populations. The validated nomogram integrates these biomarkers to stratify patients into distinct risk groups, facilitating tailored thiopurine therapy.

PMID:40774024 | DOI:10.1016/j.dmd.2025.100119

Discov Oncol. 2025 Aug 7;16(1):1491. doi: 10.1007/s12672-025-03377-3.

ABSTRACT

BACKGROUND: High abundance of eosinophils has been proved to associated with favorable disease progression in non-small cell lung cancer (NSCLC) in the previous observational studies, but the causal relationship remains unclear. It is also unclear whether white blood cell (WBC) counts are essential for the risk of NSCLC.

METHODS: Using multiple methods of Mendelian randomization (MR), we assessed the causality of WBC count, particularly basophil, eosinophil, monocyte, lymphocyte, and neutrophil counts on the risk of NSCLC, which includes squamous carcinoma and adenocarcinoma. Single cell RNA-sequencing and RNA-sequencing analysis illustrate the underline mechanism of the causality and its biological effects.

RESULTS: Univariable MR analysis indicated the protective effect of elevated eosinophil counts on NSCLC and adenocarcinoma subtype. The protective effect of eosinophils persisted even after adjusting. The protective functions mainly effected by immune activating, and it contribute to better survival and favorable response to immune therapy. Univariate MR analysis also states the risk role of neutrophil. Sequencing based analysis proved the immune inhibit functions of neutrophil, which lead to worse survival and immune treatment response.

CONCLUSION: Our study indicated a correlation between circulating eosinophil counts, neutrophil counts, and the development of NSCLC. And sequencing analysis confirm this relationship and illustrated the underline mechanism.

PMID:40773084 | DOI:10.1007/s12672-025-03377-3

Pharmacogenomics. 2025 Aug 7:1-16. doi: 10.1080/14622416.2025.2541404. Online ahead of print.

ABSTRACT

Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation (HSCT), contributing to increased morbidity and mortality. Thus, continuous development of novel prophylactic and therapeutic approaches is crucial for GvHD prevention and management. With the current development of personalized medicine and a more patient-oriented approach, pharmacogenetics has the potential to become a critical factor in optimizing the prophylaxis and treatment of GvHD. This review explores the role of pharmacogenetic variants in prophylaxis and management of GvHD, including drugs such as calcineurin inhibitors, methotrexate, mycophenolate mofetil, cyclophosphamide, and corticosteroids. A deeper understanding of these genetic factors could help in developing a more personalized approach to GvHD management, improving clinical outcomes and minimizing adverse effects. This review underscores the need for more pharmacogenetic association studies, as well as for incorporating pharmacogenetic testing into clinical practice to refine drug selection and dosing strategies in GvHD treatment.

PMID:40772575 | DOI:10.1080/14622416.2025.2541404

Cureus. 2025 Jul 7;17(7):e87436. doi: 10.7759/cureus.87436. eCollection 2025 Jul.

ABSTRACT

Osteoporosis is a chronic skeletal disorder marked by reduced bone mineral density (BMD) and increased fracture risk, posing a substantial global health burden. Traditionally considered multifactorial, growing evidence highlights a significant genetic contribution across both early-onset monogenic and adult-onset polygenic forms. Understanding the molecular and genetic architecture of osteoporosis is crucial for guiding targeted diagnostics and developing personalised therapeutic strategies. This review aimed to: (1) identify and summarise genetic mutations and polymorphisms associated with osteoporosis, classifying them into monogenic and multifactorial causes; (2) distinguish between syndromic and non-syndromic forms of genetically influenced osteoporosis; (3) evaluate how specific genetic variations influence the risk, onset, and severity of osteoporosis, particularly in postmenopausal populations; (4) examine current anti-resorptive and anabolic treatments in the context of genetic backgrounds; and (5) identify gaps in knowledge to guide future research into genetics-based screening and individualised treatment. A comprehensive literature search was conducted across PubMed, Embase, CINAHL, and the Cochrane Library for studies published between 2000 and 2025. Medical Subject Headings (MeSH) and free-text keywords were used to retrieve peer-reviewed articles, clinical trials, genetic association studies, and systematic reviews. Eligible studies explored genetic variants, bone signalling pathways (e.g., WNT/β-catenin, Notch), or pharmacological therapies in relation to BMD, fracture incidence, or osteogenesis. Data were extracted and thematically analysed under the following three core domains: genetic and molecular mechanisms, osteogenesis and bone remodelling, and treatment responses linked to genetic profiles. The review identified a wide spectrum of genetic contributors to osteoporosis. Monogenic forms, often syndromic, were linked to mutations in genes such as COL1A1, COL1A2, and WNT1, whereas multifactorial osteoporosis, particularly postmenopausal, was associated with variants in LRP5, SOST, VDR, and other GWAS-identified loci. The interplay between these variants and osteogenic signalling cascades was found to influence bone homeostasis. Treatments were categorised as anti-resorptive (e.g., bisphosphonates, denosumab) or anabolic (e.g., parathyroid hormone analogues, romosozumab), with genetic factors influencing efficacy. The evidence suggests a future need for personalised therapeutic strategies based on genetic profiling. There remains a need for further large-scale studies to validate genotype-phenotype correlations and treatment responses across diverse populations. Further exploration into pharmacogenomics, microRNA regulation, and gene-targeted interventions is required. Advancing osteoporosis care will depend on integrating genetic insights into clinical practice to enable earlier diagnosis, individualised treatment, and improved patient outcomes.

PMID:40772209 | PMC:PMC12327379 | DOI:10.7759/cureus.87436

Expert Rev Clin Pharmacol. 2025 Aug 7. doi: 10.1080/17512433.2025.2545403. Online ahead of print.

ABSTRACT

INTRODUCTION: Drug-resistant epilepsy (DRE) affects 30% of epilepsy patients and represents a major therapeutic challenge. Understanding its genetic determinants is crucial for the development of effective precision medicine strategies.

AREAS COVERED: This review comprehensively evaluates genetic factors in DRE, including polymorphisms in pharmacokinetic (e.g. ABCB1) and pharmacodynamic (e.g. SCN1A), findings from genome-wide association studies (GWAS) that recently identified a significant locus at 1q42.11-q42.12 (CNIH3/WDR26) for focal DRE, the critical role of rare variants (e.g. in SCN1A, KCNQ2) and copy number variations (CNVs) in severe epileptic encephalopathies, and the emerging fields of epigenetics and polygenic risk scores (PRS).

EXPERT OPINION: Methodological limitations, including modest sample sizes and phenotypic heterogeneity, hamper genetic research on DRE. While common variants show little impact, rare variants, including CNVs, and epigenetic alterations offer promising opportunities. Future priorities include functional studies to clarify the impact of gene variants, the integration of multi-omics data and the development of advanced analytical techniques, such as machine learning and network approaches, to translate genetic discoveries into clinically actionable precision medicine and ultimately improve outcomes for DRE patients.

PMID:40771158 | DOI:10.1080/17512433.2025.2545403

Cephalalgia. 2025 Aug;45(8):3331024251353421. doi: 10.1177/03331024251353421. Epub 2025 Aug 6.

ABSTRACT

BackgroundThe present prospective, real-world study aims to assess anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) effectiveness across three consecutive one-year treatment cycles by means of a conservative intention-to-treat (ITT) analysis.MethodsWe enrolled 179 subjects (75.4% females, 51.3 years 95% confidence interval [49.2-53.4] years), 87.2% with chronic migraine and medication overuse) who started mAbs between 2018 and 2020. We recorded clinical data supported by a prospectively filled headache diary up to three one-year treatment cycles. The ITT analysis was performed with a multivariate linear mixed model considering the entire population.ResultsWe observed a marked and consistent reduction in monthly migraine days (MMDs) across the three one-year cycles of treatment: -12.7 )[-11.4 - -14.1] at end of the first year of treatment (C1), -12.4 [-11.0 - -13.8] at the end of the second year (C2) and -12.9 [-11.4 - -14.3] at the end of the third year (C3). Baseline and residual MMDs progressively decreased across the three cycles (p = 0.008): from 21.1 [19.8-22.4] to 9.6 [8.3-11.0] in C1, from 19.0 [17.4-20.5] to 9.6 [8.1-11.1] in C2, and from 15.9 [14.3-17.5] to 8.5 [6.9-10.1] in C3. At the end of C3, the 50% response rate was 38.5% (69/179).ConclusionsIn our cohort, mAbs induced a meaningful and sustained reduction in MMDs across three consecutive one-year cycles of treatment. The ITT analysis revealed a remaining high burden of disease. While confirming mAbs effectiveness in migraine prevention, these findings underscore the need for more treatment approaches and for exploring other non-CGRP dependent pathways.

PMID:40770917 | DOI:10.1177/03331024251353421

Br J Anaesth. 2025 Aug 5:S0007-0912(25)00350-2. doi: 10.1016/j.bja.2025.05.036. Online ahead of print.

ABSTRACT

INTRODUCTION: Both the dose requirements and side-effects of propofol vary significantly between individuals. Propofol is primarily metabolised by uridine 5'-diphosphate-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymatic pathways, specifically UGT1A9 (70%) and CYP2B6/CYP2C9 (29%). Genetic polymorphisms, which influence enzyme transcription and function, can influence propofol metabolism and propofol clearance and thereby potentially impact anaesthesia-related clinical outcomes. Pharmacogenomic testing can assist with individualising propofol dosing during total intravenous anaesthesia (TIVA) to improve safety and efficacy. This systematic review evaluates the impact of metabolic genetic polymorphisms on propofol clearance, dose requirements, and related clinical effects.

METHODS: A systematic search of MEDLINE, EMBASE, and the Pharmacogenomics Knowledge Base identified studies involving patients who underwent propofol-based TIVA and pharmacogenomic testing for UGT1A9, CYP2B6, and CYP2C9 genotypes.

RESULTS: Sixteen studies, involving 1779 patients receiving propofol-TIVA, were included. Of the UGT1A9 polymorphism genotypes considered, CT heterozygotes of rs72551330 (98T>C) may have a clinically relevant effect on propofol pharmacokinetics, with lower propofol clearance, lower dose requirements, and longer emergence times. CC homozygotes of rs2741045 (-440C>T) may have higher propofol clearance with faster emergence. Given currently available data, the CYP2B6 and CYP2C9 genotypes do not appear to have significant influence on propofol pharmacokinetics or anaesthesia-related clinical outcomes.

CONCLUSIONS: Genetic polymorphisms in propofol metabolism can influence the pharmacokinetics of propofol and, potentially, anaesthesia-related clinical outcomes. To confirm these observations, larger, well-designed pharmacokinetic studies exploring metabolic genetic polymorphisms as covariates are required. Such data could support pharmacogenomic-guided propofol dosing.

PMID:40769841 | DOI:10.1016/j.bja.2025.05.036

Value Health. 2025 Aug 4:S1098-3015(25)02485-4. doi: 10.1016/j.jval.2025.07.018. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the cost-effectiveness of pre-emptive CYP2D6 and CYP2C19 genotype-informed tricyclic antidepressant dosing from a societal and a healthcare perspective.

METHODS: A trial-based cost-effectiveness analysis was conducted with data from the Pharmacogenetics for Individualized Tricyclic Antidepressant dosing (PITA) study. This multicenter randomized controlled trial (n=111) compared pharmacogenetic-informed treatment (PIT) with treatment-as-usual (TAU). Quality-adjusted life years (QALY) and costs were measured at 13 and 26 weeks. Prices were based on or indexed to 2022 tariffs. Single imputation nested in the bootstrap percentile method (using 5000 bootstrap replications) was performed to address missing data and to estimate uncertainty around cost-effectiveness outcomes. Incremental Net Monetary Benefit (iNMB) was calculated based on a willingness-to-pay (WTP) of €50.000/QALY.

RESULTS: Our data showed a marginal difference of -0.0125 QALYs (95%-confidence interval (CI) -0.0404 to 0.0149, week 13) and 0.0012 QALYs (95%-CI -0.0517 to 0.0491, week 26) for PIT versus TAU. From the healthcare perspective, a cost saving of €148 (week 13) and €521 (26 week) was found for PIT. The societal perspective showed increased costs of €1300 (week 13) and €1704 (26 weeks) for PIT. The mean iNMB from a healthcare perspective was positive at 26 weeks, the other iNMB (13 weeks and societal perspective) were negative.

CONCLUSIONS: We observed marginal differences of QALYs in both the healthcare and societal perspective with cost savings from the healthcare perspective and additional cost from the societal perspective. These mixed results warrant more long-term observational studies to determine whether pre-emptive genotyping in tricyclic antidepressant dosing will be cost-effective.

PMID:40769295 | DOI:10.1016/j.jval.2025.07.018

Front Vet Sci. 2025 Jul 22;12:1511341. doi: 10.3389/fvets.2025.1511341. eCollection 2025.

ABSTRACT

Cytochrome P450 (CYP) 1A2 plays a key role in the metabolism of various drugs in dogs. However, the impact of genetic variation on differences in CYP1A2 metabolism among dogs remains unclear. Recent studies have identified variability in the copy number of the CYP1A2 gene, ranging from two to five copies. Additionally, a genetic polymorphism (stop codon) has been identified which results in the expression of an inactive protein, this has been investigated and changes in the pharmacokinetics of some clinically used drugs have been described. If these additional copies are functional, dogs with more CYP1A2 gene copies may exhibit faster drug clearance, potentially affecting appropriate drug dosing. To investigate this possibility, a well-characterized dog liver bank (N = 58) was analyzed to determine whether CYP1A2 copy number variation (CNV) correlates with CYP1A2 protein levels and enzyme activity. Real-time PCR was used to assess CYP1A2 CNV, while label-free mass spectrometry measured CYP1A2 protein concentration in liver microsomes. Theobromine N-3 demethylation was examined as a marker of canine CYP1A2 activity using commercially available recombinant CYPs and liver microsomes from dogs treated with isoform-selective enzyme inducers. Only CYP1A1 and CYP1A2 demonstrated the ability to catalyze theobromine N-3 demethylation, and this activity was induced exclusively by β-naphthoflavone. Liver microsome theobromine N-3 demethylation activity showed a moderate correlation with CYP1A2 protein levels (R s = 0.46; p = 0.0003). Among the 58 liver samples genotyped for CYP1A2 CNV, nine dogs had two copies, 20 had three copies, 23 had four copies, and six had five copies. However, CYP1A2 CNV did not significantly correlate with CYP1A2 protein concentration (R s = -0.14; p = 0.30) and showed a weak negative correlation with theobromine N-3 demethylation activity (R s = -0.45; p = 0.00035). These findings suggest that CYP1A2 CNV is not a strong predictor of increased CYP1A2 protein expression or activity. According to the literature, CNV might not be relevant, but the genetic polymorphism (stop codon) could potentially be. The studies available show relationships between the stop codon and protein inactivity in the metabolizing of clinically used drugs. Further studies are necessary to validate these preliminary results.

PMID:40765748 | PMC:PMC12322894 | DOI:10.3389/fvets.2025.1511341

Pharmacotherapy. 2025 Aug 5. doi: 10.1002/phar.70041. Online ahead of print.

ABSTRACT

OBJECTIVES: Second-generation antipsychotic (SGA) medications are frequently prescribed for mental health conditions; however, they are associated with an increased risk of metabolic syndrome (MetS). We aimed to identify genetic associations of SGA-associated MetS (SGA-MetS) using genome-wide approaches within the UK Biobank. We also set out to evaluate if genetically predicted obesity is associated with an increased risk of SGA-MetS.

METHODS: We defined SGA-MetS based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria using cross-sectional data from 1318 UK Biobank participants who reported being on an SGA medication. An SGA-MetS case was defined as meeting three or more of the five NCEP-ATP III criteria. We performed a genome-wide association study (GWAS) and gene-based analysis to identify significant variants and gene associations. We computed the polygenic risk score (PGS) for body mass index (BMI) using 2,100,302 variants validated for obesity and metabolic traits from imputed single-nucleotide polymorphism (SNP) data. We tested the association of PGS-BMI with SGA-MetS using logistic regression.

RESULTS: GWAS identified suggestive associations (p < 1 × 10-5) on chromosome 15. The variant rs12914956 in CHD2 was associated with increased risk of SGA (odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.4-2.4, p = 3.6 × 10-7). The gene-based analysis identified significant gene associations with RBFOX1 (p = 4.85 × 10-7), PTPRD (p = 7.6 × 10-7), CSMD1 (p = 2.2 × 10-6), and CHD2 (p = 1.3 × 10-6). The PGS-BMI (β = 0.23, p = 6.8 × 10-5), was associated with increased MetS in a model adjusted for age, sex, physical activity, alcohol consumption, antidepressant medications, schizophrenia diagnosis, and principal components of ancestry.

CONCLUSION: Using a gene-based analysis, we identified significant gene associations with SGA-MetS that have been previously associated with obesity and metabolic traits. The PGS-BMI was associated with MetS, suggesting that a genetic predisposition to a higher BMI may increase the risk of SGA-MetS. Future research should replicate the findings in a larger dataset with more diverse populations.

PMID:40762455 | DOI:10.1002/phar.70041

Pharmacogenet Genomics. 2025 Aug 5. doi: 10.1097/FPC.0000000000000573. Online ahead of print.

ABSTRACT

It is unknown how many people in the US have had pharmacogenetic (PGx) testing and whether people want to be tested. We conducted a nationally representative survey of the general US adult population to determine the prevalence of adults that have had PGx testing using a validated confidential online survey, the Non-Medical Use of Prescription Drugs Program. A weighted logistic regression was used to test health characteristics associated with PGx testing and determine those who desire to be tested. The analysis included 29 146 individuals who completed the survey, which represents approximately 260 000 000 adults in the US. The prevalence of US adults who have been PGx tested is 6.6% [95% confidence interval (CI): 6.2-7.0]. Only 32.2% (95% CI: 31.5-32.9), an estimated 79 million individuals, desired PGx testing. Adults who had or want PGx testing were more likely to be female, have higher education, be students, current or former members of the military, use medications, and have a mental health disorder. The prevalence of adults who have been PGx tested remains low in the US. There are knowledge gaps about the benefits of PGx testing that must be bridged to increase implementation.

PMID:40762070 | DOI:10.1097/FPC.0000000000000573

Front Immunol. 2025 Jul 21;16:1609740. doi: 10.3389/fimmu.2025.1609740. eCollection 2025.

ABSTRACT

INTRODUCTION: Ulcerative colitis (UC) is characterized by aberrant immune responses involving multiple inflammatory pathways, including JAK/STAT signaling. However, the specific roles and interactions of individual components within this pathway remain unclear.

METHODS: We conducted a prospective, observational, single-center study enrolling 61 adult UC patients undergoing routine colonoscopy with endoscopic activity (Mayo Endoscopic Score > 0). Paired biopsies from inflamed and non-inflamed colonic mucosa were collected. Phosphorylation levels of JAK1, JAK2, JAK3, TYK2, STAT1, STAT3, and STAT4 were quantified by Western blot.

RESULTS: Inflamed tissue showed significantly increased phosphorylation of JAK2, JAK3, TYK2, STAT1, STAT3, and STAT4 compared to non-inflamed mucosa (p < 0.05), while JAK1 levels did not differ significantly. Correlation analysis revealed coordinated activation among JAK2, JAK3, TYK2, and STAT3, suggesting interdependent roles. Notably, male patients exhibited significantly higher activation of JAK2 and STAT3 than female patients (p < 0.05).

DISCUSSION: These findings highlight a heterogeneous but important involvement of the JAK/STAT pathway in UC pathophysiology. The observed sex-specific differences and coordinated activation patterns suggest the value of personalized therapeutic approaches targeting specific components of this pathway.

PMID:40761789 | PMC:PMC12318950 | DOI:10.3389/fimmu.2025.1609740

Toxicol Rep. 2025 Jul 20;15:102093. doi: 10.1016/j.toxrep.2025.102093. eCollection 2025 Dec.

ABSTRACT

The goal of this study was to explore associations between single-nucleotide polymorphisms (SNPs) and umbilical cord blood concentrations of buprenorphine and its metabolites following maternal administration. This is a sub-study of a prospective observational cohort investigation which included pregnant women receiving buprenorphine for opioid use disorder during pregnancy. Following delivery, umbilical cord blood samples were collected and genotyped using a pharmacogenetic panel. The drug and metabolite concentrations were analyzed through liquid chromatography-mass spectrometry, and genetic association analysis was completed using PLINK software. The included neonates (n = 14) had a mean birth weight of 3.00 ± 0.39 kg and were born to mothers receiving a mean buprenorphine dose of 10.29 ± 6.22 mg. Ten concentration groupings (drug, single metabolite, as well as drug/metabolite(s) combinations) produced 18 unique SNP associations. Two significant associations included variations in CYP3A4 and UGT1A1, which play a role in the metabolism of buprenorphine. These preliminary findings suggest potential pharmacogenetic factors influencing fetal drug exposure, warranting larger studies to validate associations and explore clinical implications for neonatal outcomes.

PMID:40761746 | PMC:PMC12319250 | DOI:10.1016/j.toxrep.2025.102093