BMC Psychiatry. 2025 Jun 6;25(1):590. doi: 10.1186/s12888-025-07033-6.

ABSTRACT

INTRODUCTION: Sertraline, a widely prescribed antidepressant, has considerable variability in serum concentrations. This retrospective study aimed to identify key determinants influencing sertraline concentrations, with a special focus on age-related differences.

METHODS: We conducted a retrospective analysis of TDM data from 1076 patients (474 children/adolescents and 602 adults) collected between 2018 and 2024. Multivariable generalized linear regression and restricted cubic spline models were used to examine the relationships between clinical parameters and sertraline concentrations.

RESULTS: The daily dose and aspartate aminotransferase (AST) level were positively correlated with the sertraline concentration in both age groups. Sex had a significant effect, with women exhibiting 43% (P = 0.001) and 37% (P = 0.001) higher concentrations than men in the child/adolescent and adult groups, respectively. In children and adolescents, the albumin (Alb) level and neutrophil (NEUT) count also considerably influence concentrations. CYP2C19 poor metabolizers (PMs) tended to be present at relatively high concentrations, but the difference was not statistically significant. Among child and adolescent patients, significant differences in dose-adjusted serum concentration (C/D) values (P = 0.0291) were observed across different CYP2C19 phenotypes, with PMs exhibiting higher C/D values. In a cohort of 593 patients who underwent high-sensitivity C-reactive protein (hsCRP) testing, a nonlinear, U-shaped correlation between hsCRP levels and sertraline concentrations was identified in children and adolescents.

DISCUSSION: By identifying key factors such as daily dose, sex and AST levels, clinicians can develop tailored treatment plans for individual patients. These findings underscore the need for further research to elucidate the interplay between sertraline metabolism and patients' physiological and pathological characteristics.

PMID:40481507 | DOI:10.1186/s12888-025-07033-6

J Neurol Neurosurg Psychiatry. 2025 Jun 6:jnnp-2025-335868. doi: 10.1136/jnnp-2025-335868. Online ahead of print.

NO ABSTRACT

PMID:40480807 | DOI:10.1136/jnnp-2025-335868

Lancet Diabetes Endocrinol. 2025 Jun 3:S2213-8587(25)00121-4. doi: 10.1016/S2213-8587(25)00121-4. Online ahead of print.

NO ABSTRACT

PMID:40480241 | DOI:10.1016/S2213-8587(25)00121-4

JCO Precis Oncol. 2025 Jun;9:e2500062. doi: 10.1200/PO-25-00062. Epub 2025 Jun 6.

ABSTRACT

PURPOSE: The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common DPYD variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated.

PATIENTS AND METHODS: Patients were grouped into four variant categories (DPYD*2A [c.1905+1G>A], DPYD*13 [c.1679T>G], c.2846A>T [p.D949V], c.1236G>A/HapB3 [p.E412E]) and a DPYD wild-type control group. Uracil loading tests were used for phenotyping. Variant patients started on a 50% reduced 5-FU dose. On the basis of steady-state 5-FU plasma concentrations, dose adjustments were made during cycles 2-4 until an 5-FU target AUC0-46h of 20-30 mg × h/L was achieved, if tolerated.

RESULTS: Twenty-six wild-type controls and 34 DPYD variant patients were included: 16 with c.1236G>A/HapB3, eight with c.1905+1G>A, eight with p.D949V, and two with c.1679T>G. Heterozygous carriers of c.1905+1G>A (DPYD*2A) and c.1679T>G (DPYD*13) displayed significant reduced uracil metabolism. The impact on uracil clearance was highly variable in p.D949V but only minor in c.1236G>A/HapB3 variants. In all, 65% of wild-type controls had 5-FU exposure within target range on a 100% dose (mean, 23.2; IQR, 6.6). In 97% of all variant patients, the 50% reduced dose resulted in 5-FU underexposure, with a median AUC of 10.6 mg × h/L (IQR, 3.2). Dose escalation to 70% or higher was tolerated in most patients, reaching the target AUC in 68% of patients.

CONCLUSION: The current CPIC guidelines are overly conservative for c.1236G>A/HapB3 and most p.D949V variants. A 75% starting dose is more appropriate for most c.1236G>A/HapB3 carriers. We recommend 5-FU therapeutic drug monitoring in all patients with DPYD variants to achieve optimal 5-FU exposure.

PMID:40479625 | DOI:10.1200/PO-25-00062

Eur J Clin Pharmacol. 2025 Jun 6. doi: 10.1007/s00228-025-03858-y. Online ahead of print.

ABSTRACT

PURPOSE: The main objective of this study was to systematically evaluate the effectiveness of pharmacogenomics-guided treatment (PGxT) and treatment-as-usual (TAU) in schizophrenia management through two key indicators: medication adherence and antipsychotic switching rate.

METHODS: The study cohort comprised individuals with schizophrenia who were hospitalized between April 2022 and March 2024. The cohort was stratified into two groups: the PGxT and TAU. To address potential confounding between the groups, propensity score matching (PSM) was applied. The primary outcome measures were the proportions of patients with good medication adherence (≥ 80%) at three and six months after discharge and the antipsychotic switching rate.

RESULTS: Among the 420 patients in the PGxT and TAU groups obtained through propensity score matching, the proportions of patients with good medication adherence (≥ 80%) was 49.76% at three months and 33.10% at six months, with a significant difference between the follow-up periods (P < 0.001). During the three-month observation period, the proportion of patients demonstrating good adherence were significantly different (55.24% in PGxT group vs. 44.29% in TAU group; P = 0.032). The difference was also significant after six months (44.76% in PGxT group vs. 21.43% in TAU group; P < 0.001). Furthermore, the proportion of antipsychotic switching rate was lower in the PGxT group (25.71%) than in the TAU group (41.90%) (P < 0.001).

CONCLUSION: This study observed an association between PGxT and higher adherence as well as lower medication switching rate in patients with schizophrenia, which suggests potential clinical utility of PGx testing.

PMID:40478260 | DOI:10.1007/s00228-025-03858-y

Anesthesiol Perioper Sci. 2023;1(2):16. doi: 10.1007/s44254-023-00018-2. Epub 2023 Jun 14.

ABSTRACT

The list of drugs patients may be exposed to during the perioperative and postoperative periods is potentially extensive. It includes induction agents, neuromuscular blocking drugs (NMBDs), opioids, antibiotics, sugammadex, colloids, local anesthetics, polypeptides, antifibrinolytic agents, heparin and related anticoagulants, blue dyes, chlorhexidine, and a range of other agents depending on several factors related to individual patients' clinical condition and progress in the postoperative recovery period. To avoid poor or ultrarapid metabolizers to a particular drug (for example tramadol and codeine) or possible adverse drug reactions (ADRs), some drugs may need to be avoided during or after surgery. This will be the case for patients with a history of anaphylaxis or other adverse events/intolerances to a known drug. Other drugs may be ceased for a period before surgery, e.g., anticoagulants that increase the chance of bleeding; diuretics for patients with acute renal failure; antihypertensives relative to kidney injury after major vascular surgery; and serotonergic drugs that together with some opioids may rarely induce serotonin toxicity. Studies of germline variations shown by genotyping and phenotyping to identify a predisposition of genetic factors to ADRs offer an increasingly important approach to individualize drug therapy. Studies of associations of human leukocyte antigen (HLA) genes with some serious delayed immune-mediated reactions are ongoing and variations of drug-metabolizing cytochrome CYP450 enzymes, P-glycoprotein, and catechol-O-methyltransferase show promise for the assessment of ADRs and non-responses to drugs, particularly opioids and other analgesics. Surveys of ADRs from an increasing number of institutions often cover small numbers of patients, are retrospective in nature, fail to clearly identify culprit drugs, and do not adequately distinguish immune-mediated from non-immune-mediated anaphylactoid reactions. From the many surveys undertaken, the large list of agents identified during and after anesthesia and surgery are examined for their ADR involvement. Drugs are classified into those most often involved, (NMBD and antibiotics); drugs that are becoming more frequently implicated, namely antibiotics (particularly teicoplanin), and blue dyes; those becoming less frequently involved; and drugs more rarely involved in perioperative, and postoperative adverse reactions but still important and necessary to keep in mind for the occasional potential sensitive patient. Clinicians should be aware of the similarities between drug-induced true allergic type I IgE/FcεRI- and pseudoallergic MRGPRX2-mediated ADRs, the clinical features of each, and their distinguishing characteristics. Procedures for identifying MRGPRX2 agonists and diagnosing and distinguishing pseudoallergic from allergic reaction mechanisms are discussed.

PMID:40476920 | PMC:PMC10264870 | DOI:10.1007/s44254-023-00018-2

J Allergy Clin Immunol Glob. 2025 Apr 22;4(3):100485. doi: 10.1016/j.jacig.2025.100485. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Peanut is a major cause of food allergy. HLA genes have been consistently associated with peanut allergy in association studies. To date, however, there have been very few genetic studies of peanut allergy in non-Hispanic Black (Black) individuals, a group disproportionately affected by food allergy.

OBJECTIVE: Our aim was to study the relationship between HLA alleles and peanut allergy among Black individuals.

METHODS: The analysis consisted of Black participants from the Study of Asthma-Related Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE), a large cohort of individuals from metropolitan Detroit. At the time of enrollment, participants provided detailed food allergy histories, including symptoms. Four-digit resolution HLA allele calls were made using whole genome sequence data.

RESULTS: The cases consisted of 119 individuals with reported peanut allergy and 59 individuals with peanut-related anaphylaxis; the comparison group consisted of 2640 individuals without reported food allergy. HLA-DRB1∗13:02 was the most significant allele associated with peanut allergy (adjusted odds ratio = 1.94 [95% CI = 1.28-2.93]), and HLA-DQA1∗01:02 was the top association with peanut-related anaphylaxis (aOR = 1.67 [95% CI = 1.14-2.44]). Amino acid polymorphisms at position 71 in the binding groove of HLA-DRB1 were associated with peanut allergy and estimated to affect peanut allergen binding affinity.

CONCLUSIONS: In a cohort of Black individuals, this study independently identified the same associations of peanut allergy and HLA that were previously observed in non-Hispanic White individuals. Our findings suggest that specific HLA binding groove amino acid polymorphisms may confer similar peanut allergy risk across population groups and HLA alleles.

PMID:40476093 | PMC:PMC12139416 | DOI:10.1016/j.jacig.2025.100485

Br J Gen Pract. 2025 Jun 5:BJGP.2024.0806. doi: 10.3399/BJGP.2024.0806. Online ahead of print.

ABSTRACT

Background Pharmacogenetics has the potential to optimise drug therapy and reduce adverse drug effects (ADEs) by tailoring treatment to a patient's genotype, particularly for chronic disorders managed in general practice (GP). However, the adoption of pharmacogenetics in GP remains slow. Aim This study aimed to evaluate the reproducibility of previously reported associations between genomic variants and medically important adverse drug effects (MIADEs) associated with high-risk medications in GP. Design and setting A retrospective study using data from the UK Biobank (UKBB), a population-based cohort of over 500,000 community-based participants. Method We identified high-risk medications prescribed in GP by linking serious ADEs from the Yellow Card database with English GP prescription data. These high-risk medications were then cross-examined with genomic variants associated with MIADEs from the Pharmacogenomics Knowledgebase (PharmGKB), to select variant-drug pairs for investigation within the UKBB. Results From 78 high-risk medications prescribed in GP and 56 PharmGKB annotations linked to MIADE risk, SLCO1B1 rs4149056 was the only variant with guideline-based prescribing recommendations. This variant, along with others of lower evidence levels, was analysed in the UKBB. No genotype-treatment interaction was observed for SLCO1B1 rs4149056 and statin-related muscle toxicity. Similarly, no interactions were detected for the remaining variants in either secondary or exploratory analyses. Conclusion No statistically significant genotype-treatment interactions were observed for MIADE risk associated with high-risk medications in GP. However, the limited predictive value of the assessed variants may reflect underlying phenotypic imprecision and methodological limitations. Hence, further research is needed to validate these results.

PMID:40473432 | DOI:10.3399/BJGP.2024.0806

Nurse Pract. 2024 Dec 1;49(12):33-34. doi: 10.1097/01.NPR.0000000000000263. Epub 2024 Nov 21.

NO ABSTRACT

PMID:40471158 | DOI:10.1097/01.NPR.0000000000000263

Nurse Pract. 2024 Dec 1;49(12):24-33. doi: 10.1097/01.NPR.0000000000000256. Epub 2024 Nov 21.

ABSTRACT

A pharmacogenomics-informed prescribing strategy examines genetic variations in individual patients for more personalized selection and dosing of psychiatric medications for which a clinical evidence base and/or clinical guidelines exist. Clinicians who prescribe psychiatric medications should be aware of the pharmacogenomic evidence base and existing guidelines relevant to medication selection, dosing, and interactions to ensure safe and effective treatment. Although pharmacogenomic testing does not replace current prescribing strategies, when used alongside them, it acts as a valuable clinical decision support tool that can improve the selection and dosing of specific psychiatric medications.

PMID:40471157 | DOI:10.1097/01.NPR.0000000000000256

Front Pharmacol. 2025 May 21;16:1564124. doi: 10.3389/fphar.2025.1564124. eCollection 2025.

ABSTRACT

Idiosyncratic hepatotoxicity is a type of drug-induced liver injury (DILI) that is unpredictable and clinically severe, and amoxicillin clavulanate (AC) is the most implicated drug in DILI worldwide. The clinical manifestations of amoxicillin clavulanate-induced liver injury (AC-DILI) are fatigue and jaundice, which some allergic features may accompany, but autoimmune phenomena are uncommon. Here, we describe a special case report of a patient with AC-DILI accompanied by autoimmune phenomena for the first time. The patient was a middle-aged Chinese woman who developed liver damage after taking AC for a period of time, with a RUCAM score of 6. The patient tested positive for antinuclear antibodies and had elevated levels of IgG. Human leukocyte antigen (HLA)-targeted sequencing results showed that the patient did not carry known AC-DILI-related HLA polymorphisms, but Sanger sequencing suggested that the patient had the ERAP2 rs1363907 mutation, which may be a pathogenic factor of AC-DILI in the patient. The patient's progress notes, disease diagnosis, and treatment are summarized, and the role of ERAP2 pathogenic mutation rs1363907 in AC-DILI is discussed.

PMID:40469972 | PMC:PMC12133467 | DOI:10.3389/fphar.2025.1564124

Front Oral Health. 2025 May 21;6:1489823. doi: 10.3389/froh.2025.1489823. eCollection 2025.

ABSTRACT

INTRODUCTION: Periodontitis is a chronic inflammatory disease characterized by the progressive destruction of the tooth's supporting tissues, driven by complex interactions between periodontopathogenic bacteria, environmental factors, and the host immune response. MicroRNAs (miRNAs) have emerged as key modulators of inflammatory pathways and are increasingly recognized for their role in the pathogenesis of periodontitis. Their deregulation in this disease suggests potential therapeutic applications targeting miRNA expression. Natural compounds such as isodrimeninol, derived from Drimys winteri (Dw), may offer novel approaches to modulate miRNA activity due to their antiinflammatory properties. However, no studies have previously linked this sesquiterpene to miRNA regulation in periodontitis. This study investigates the in vitro effects of isodrimeninol on six miRNAs (miR-17-3p, miR-21-3p, miR-21-5p, miR-146a-5p, miR-155-5p, and miR-223-3p) associated with periodontitis using two cellular models.

METHODS: Saos-2 cells (osteoblast-like cells) and periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs). Both cell types were stimulated with lipopolysaccharide (LPS) to induce inflammation and treated with isodrimeninol and resveratrol for comparison.

RESULTS: Isodrimeninol reduced Interleukin-1beta (IL-1β) and Interleukin-6 (IL-6) gene expression and caused differential expression patterns of the miRNAs examined, upregulating miR-146a-5p and miR-223-3p, while downregulating miR-17-3p, miR-21-3p, miR-21-5p, and miR-155-5p (p < 0.05).

CONCLUSION: These findings indicate a connection between miRNAs, periodontitis, and the regulation of inflammation by isodrimeninol, providing potential opportunities for the treatment. However, further validation is needed to confirm these results.

PMID:40469388 | PMC:PMC12133741 | DOI:10.3389/froh.2025.1489823

Front Immunol. 2025 May 21;16:1521794. doi: 10.3389/fimmu.2025.1521794. eCollection 2025.

ABSTRACT

Tumor necrosis factor alpha inhibitors (TNFi) are biologic drugs that target TNFα, a key pro-inflammatory cytokine, to suppress disease activity and alleviate symptoms of various autoimmune diseases, including inflammatory bowel disease. This review focuses on the five US FDA-approved TNFi including the monoclonal antibodies Infliximab, Adalimumab, Golimumab, Certolizumab pegol and the soluble TNFα receptor fusion protein Etanercept, with a brief mention of other available biosimilars to TNFi. The review aims to summarize the recent evidence on the pharmacokinetics, pharmacodynamics, and pharmacogenomics of TNFi with a particular focus on Human Leukocyte Antigen (HLA) variants in terms of their genetic contribution to the response to TNFi. HLA variants have been linked to heterogeneity in the efficacy and safety of TNFi among patients. Building on the summarized evidence, the last part of the review discusses the potential clinical utility of testing for pharmacogenetic variants that are linked to the response to TNFi prior to the drug prescription, and it also addresses the future directions to achieve personalized treatment for TNFi users.

PMID:40469293 | PMC:PMC12133927 | DOI:10.3389/fimmu.2025.1521794

Clin Pharmacol Ther. 2025 Jun 4. doi: 10.1002/cpt.3736. Online ahead of print.

ABSTRACT

Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement. Over time, many of these challenges have been overcome, and clinical pharmacogenetic testing has subsequently reached broader implementation. Despite this progress, several barriers remain that block further adoption. This narrative review used authors' expertise and experience to identify and describe current barriers to pharmacogenetic implementation across seven domains in the United States: equity and inclusion; guidelines and supporting evidence; regulatory agency oversight; payer coverage and insurance; availability of quality pharmacogenetic tests; electronic health records; and provider and patient education. Within each domain, it revisits past successes and challenges and explores remaining barriers. We also propose solutions to address ongoing challenges across these domains, including further expansion of recommendations beyond pharmacogenetic-specific guidelines, standards for designing clinical decision support tools, and broader pharmacogenetics education. Addressing these remaining obstacles directs work to enable broader adoption of clinical pharmacogenetic implementation to ultimately improve patient outcomes.

PMID:40468601 | DOI:10.1002/cpt.3736

Biochem Pharmacol. 2025 Jun 2:117016. doi: 10.1016/j.bcp.2025.117016. Online ahead of print.

ABSTRACT

The pregnane X receptor (PXR) activator rifampicin (RIF) plays a critical role in drug-drug interactions (DDIs) by inducing cytochrome P450 (CYP) 3A4 expression. Increasing evidence indicates that n6-methyladenosine (m6A) modification is involved in the regulation of CYP basal expression. Here, we showed its effect on RIF-induced CYP3A4 expression. This study found that m6A levels and methyltransferase-like 3 (METTL3) expression were upregulated in HepG2 and LS174T cells treated with RIF, as well as in mice treated with pregnenolone-16α-carbonitrile (PCN, a typical PXR activator in mice), associated with the expression of CYP3A4 and Cyp3a11 (mouse homolog of human CYP3A4). Specifically, knockdown or overexpression of METTL3 downregulated and upregulated the basal and RIF-induced expression of CYP3A4, respectively. Similar results were obtained in a mouse model with liver-specific knockdown of Mettl3 (homolog of human METTL3) treated with PCN, indicating the involvement of m6A methylation in RIF-induced CYP3A4 expression. Mechanistically, METTL3 promotes PXR nuclear translocation and protein translation, while potentially affecting CYP3A4 mRNA stability through its binding to CYP3A4 mRNA (enhanced by RIF), thereby contributing to RIF-induced upregulation of CYP3A4 expression. Functionally, we observed that METTL3 knockdown or treatment with the METTL3 inhibitor STM2457 reduced the cytotoxicity induced by RIF combined with ritonavir. In conclusion, this study identified a novel mechanism of m6A modification in the regulation of RIF-induced CYP3A4 expression, providing valuable insights into CYP3A4-mediated DDIs.

PMID:40466953 | DOI:10.1016/j.bcp.2025.117016

EBioMedicine. 2025 Jun 3;117:105785. doi: 10.1016/j.ebiom.2025.105785. Online ahead of print.

ABSTRACT

With the rapid evolution of precision medicine, diagnostic, and therapeutic strategies for lupus nephritis (LN) are progressively shifting towards greater personalisation and accuracy. On the diagnostic front, the discovery and deployment of novel molecular biomarkers, together with the integration of artificial intelligence (AI) and machine learning (ML) technologies, have opened new avenues for delineating disease subtypes and forecasting treatment responses, thereby optimising clinical decision-support systems. In the therapeutic domain, innovations in targeted biologics and the precise application of diverse targeted modalities have shown promise in enhancing efficacy while reducing adverse effects. The triadic synergy of molecular biomarker breakthroughs, iterative advances in intelligent computational tools and pioneering targeted therapies is poised to usher LN in a new era of customised diagnosis and intervention.

PMID:40466435 | DOI:10.1016/j.ebiom.2025.105785

Hum Immunol. 2025 Jun 3;86(4):111333. doi: 10.1016/j.humimm.2025.111333. Online ahead of print.

ABSTRACT

BACKGROUND: High HIV/AIDS prevalence in China calls for personalized therapies like pharmacogenomics to improve antiretroviral treatment efficacy. This study explored associations between single nucleotide polymorphisms (SNPs) and outcomes of highly active antiretroviral therapy (HAART) in HIV-1 patients.

METHODS: We collected blood samples and clinical data from 503 HIV-1-infected patients undergoing HAART for 12 months. Using bioinformatics databases, we identified 81 SNPs in genes related to drug transport, immunity, and HIV infection. These SNPs were genotyped and correlated with highly active antiretroviral therapy efficacy and side effects using the Mass Array system and SPSS. FDR multiple correction was performed on all positive SNPs.

RESULTS: After 12 months of highly active antiretroviral therapy with Tenofovir disoproxil fumarate (TDF) and Lamivudine (3TC), the patients showed significant viral suppression and immune recovery.CD4 response was associated with GABPB1 rs12594956 (OR = 0.378, P = 0.002, FDR-P = 0.032). Viral load response was associated with CCR5 rs2734648 (OR = 22.812, P = 0.018, FDR-P = 0.045), IL2RA rs1323657 (OR = 18.312, P = 0.020, FDR-P = 0.045) and IL2 rs2069772(OR = 139.173, P = 0.002, FDR-P = 0.02). Rash risk was elevated with SLC22A2 rs316009 (OR = 16.077, P = 0.013, FDR-P = 0.048) and NRF2 rs1806649 (OR = 35.328, P = 0.002, FDR-P = 0.011). Liver toxicity was associated with SLC22A2 rs316009 (OR = 10.057, P = 0.005, FDR-P = 0.030). IFNL3 rs4803219 (OR = 2.461, P = 0.008, FDR-P = 0.024) and NRF1 rs11557288 (OR = 2.106, P = 0.035, FDR-P = 0.035) were linked to syphilis co-infection. NRF1 rs6949152 (OR = 0.329, P = 0.002, FDR-P = 0.030) were associated with HBsAg positivity in HBV co-infection.These results were verified in dominant or recessive models.

CONCLUSION: This study establishes a foundation for using SNPs as predictive biomarkers for highly active antiretroviral therapy outcomes in Chinese HIV/AIDS patients, offering insights into personalized treatment strategies.

PMID:40466234 | DOI:10.1016/j.humimm.2025.111333

Sci Adv. 2025 Jun 6;11(23):eadt0539. doi: 10.1126/sciadv.adt0539. Epub 2025 Jun 4.

ABSTRACT

We addressed the underrepresentation of non-European populations in genome-wide association studies (GWASs) by building HiGenome, a large-scale genetic resource for the Taiwanese Han population. Using a custom genotyping array, we integrated deidentified electronic medical records (2003 to 2021) with genomic data to enable GWASs, phenome-wide association studies, and polygenic risk score (PRS) analysis. Among 413,000 participants, 323,397 passed ancestry and quality control filtering. GWASs covered 1085 traits, focusing on diseases prevalent in Taiwan such as type 2 diabetes, chronic kidney disease, gout, and alcoholic liver damage. PRSs were calculated for 238 traits, with the strongest associations observed in musculoskeletal disorders. Incorporating PRS into clinical practice supports early risk prediction and personalized prevention. To further expand translational value, we also conducted pharmacogenomic analysis and human leukocyte antigen typing. HiGenome offers a large-scale genetic and clinical dataset from the Taiwanese Han population, supporting population-specific analyses and precision medicine development in East Asia. The hospital-based design enables continuous follow-up and longitudinal data expansion.

PMID:40465716 | DOI:10.1126/sciadv.adt0539

Clin Transl Sci. 2025 Jun;18(6):e70255. doi: 10.1111/cts.70255.

ABSTRACT

Pharmacogenetics is a promising strategy to facilitate individualized care for patients with Major Depressive Disorder (MDD). Research is ongoing to identify the optimal genetic markers for predicting outcomes to antidepressant therapies. The primary aim of this systematic review was to summarize antidepressant pharmacogenetic studies to enhance understanding of the genes, variants, datatypes/methodologies, and outcomes investigated in the context of MDD. The secondary aim was to identify clinical genetic panels indicated for antidepressant prescribing and summarize their genes and variants. Screening of N = 5793 articles yielded N = 390 for inclusion, largely comprising adult (≥ 18 years) populations. Top-studied variants identified in the search were discussed and compared with those represented on the N = 34 clinical genetic panels that were identified. Summarization of articles revealed sources of heterogeneity across studies and low rates of replicability of pharmacogenetic associations. Heterogeneity was present in outcome definitions, treatment regimens, and differential inclusion of mediating variables in analyses. Efficacy outcomes (i.e., response, remission) were studied at greater frequency than adverse-event outcomes. Studies that used advanced analytical approaches, such as machine learning, to integrate variants with complimentary biological datatypes were fewer in number but achieved higher rates of significant associations with treatment outcomes than candidate variant approaches. As large biological datasets become more prevalent, machine learning will be an increasingly valuable tool for parsing the complexity of antidepressant response. This review provides valuable context and considerations surrounding pharmacogenetic associations in MDD which will help inform future research and translation efforts for guiding antidepressant care.

PMID:40465332 | DOI:10.1111/cts.70255

JAMA Surg. 2025 Jun 4. doi: 10.1001/jamasurg.2025.1503. Online ahead of print.

ABSTRACT

IMPORTANCE: Pharmacogenetics can improve medication-related outcomes by optimizing efficacy and minimizing adverse effects. It is unknown whether the presence of drug-gene interactions (DGIs) at the time of surgery results in adverse outcomes in the postoperative setting.

OBJECTIVE: To determine the association of active DGIs on postsurgical outcomes following vascular surgery procedures.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of Veterans Affairs (VA) hospital patients participating in the Million Veteran Program who had a vascular procedure documented in the VA Surgical Quality Improvement Program (VASQIP) from January 1, 2011, to December 31, 2022. Data analysis was performed from June 1, 2023, to October 31, 2024.

EXPOSURE: Receipt of drugs impacted by pharmacogenetic variants 30 days prior to and up to 7 days following the vascular surgery procedure.

MAIN OUTCOMES AND MEASURES: Clinical outcomes collected as part of VASQIP, including length of stay (LOS), 30-day readmission, composite of myocardial infarction, stroke, and myocardial injury after noncardiac surgery, and 30-day postoperative death.

RESULTS: Among 10 098 patients (mean [SD] age, 68.8 [8.3] years; 1581 [15.7%] Black [self-reported]; 9884 [97.9%] male), 5020 (49.7%) had a DGI. The most common DGIs included proton pump inhibitors with CYP2C19, statins with SLCO1B1, and clopidogrel with CYP2C19. Compared with 0 DGIs, the presence of 1, 2, or 3 or more DGIs was associated with a longer median (IQR) LOS: with 0 DGIs, 3 (1-6) days vs 1 DGI, 3 (1-7) days (adjusted incidence rate ratio [IRR], 1.12; 95% CI, 1.10-1.14; P < .001); 2 DGIs, 3 (1-7) days (adjusted IRR, 1.22; 95% CI, 1.19-1.25; P < .001); and 3 or more DGIs, 4 (2-8) days (adjusted IRR, 1.40; 95% CI, 1.35-1.44; P < .001). The 30-day readmission rate, which was 17.4% among those with 0 DGIs, was not significantly different in those with 1 DGI (17.6%; adjusted odds ratio [aOR], 1.01; 95% CI, 0.90-1.14; P = .84) but was significantly higher in those with 2 DGIs (21.2%; aOR, 1.26; 95% CI, 1.08-1.47; P = .004) and 3 or more DGIs (25.1%; aOR, 1.61; 95% CI, 1.30-1.99; P < .001). The risk of the composite outcome, which was 3.5% in those with 0 DGIs, was not significantly different in those with 1 DGI (4.1%; aOR, 1.15; 95% CI, 0.91-1.45; P = .24) but was significantly higher in those with 2 DGIs (5.7%; aOR, 1.62; 95% CI, 1.22-2.15; P = .001) and those with 3 or more DGIs (5.5%; aOR, 1.60; 95% CI, 1.04-2.36; P = .02).

CONCLUSIONS AND RELEVANCE: The findings suggest that patients with DGIs at the time of vascular surgery have increased risk of cardiovascular morbidity, increased readmission, and longer LOS. Further work is needed to determine which DGIs contribute to these outcomes and whether preoperative pharmacogenetic testing has the potential to mitigate these risks.

PMID:40465239 | DOI:10.1001/jamasurg.2025.1503