Nat Commun. 2025 May 5;16(1):4176. doi: 10.1038/s41467-025-59490-y.

ABSTRACT

SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine (PEG-PLL-Oleic acid, PPO), and GEM-conjugated polylysine (PEG-PLL-OA-GEM, PPOGEM), PPO/PPOGEM (POEM)) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy.

PMID:40325025 | DOI:10.1038/s41467-025-59490-y

Naunyn Schmiedebergs Arch Pharmacol. 2025 May 5. doi: 10.1007/s00210-025-04155-2. Online ahead of print.

ABSTRACT

The modulation of gut microbiota presents promising therapeutic possibilities for various health conditions, ranging from gastrointestinal infections to neurodegenerative and mental health disorders. Among the available interventions, gut microbiota modulators (GMMs) such as probiotics and prebiotics have demonstrated significant potential in infection prevention and neuroprotection. Despite these encouraging findings, the clinical application of GMMs remains challenging due to safety concerns and inconsistent effectiveness across diverse patient populations. These factors create substantial barriers to the widespread adoption of microbiota-based therapies in clinical practice. To overcome these challenges and fully leverage the therapeutic potential of microbiota modulation, this review explores the feasibility of repurposing GMMs for managing multiple health disorders. A broad spectrum of microbiota-targeted strategies is examined, including dietary modifications, fecal microbiota transplantation, bacteriophage therapy, microbiome engineering, and immune system modulation. A particularly innovative approach involves integrating GMMs with pharmaceutical delivery systems to enhance therapeutic efficacy while mitigating potential adverse effects. This integrative strategy underscores the pivotal role of the gut microbiome in health and disease, supporting the development of precision medicine tailored to individual patient needs. By combining GMMs with targeted delivery mechanisms, this approach not only improves treatment effectiveness but also addresses critical concerns regarding safety and patient variability. Furthermore, this review outlines future research directions within the rapidly evolving field of microbiota modulation, emphasizing the necessity of comprehensive clinical trials and long-term safety evaluations. By critically assessing both the challenges and opportunities associated with microbiota-based interventions, this study provides a strategic framework for translating experimental research into viable clinical applications. A holistic approach to gut microbiota modulation has the potential to redefine treatment paradigms, offering personalized therapeutic strategies for a wide range of disorders and advancing the broader field of precision medicine.

PMID:40323507 | DOI:10.1007/s00210-025-04155-2

Drug Des Devel Ther. 2025 Apr 30;19:3589-3610. doi: 10.2147/DDDT.S505751. eCollection 2025.

ABSTRACT

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of cardiovascular-related deaths. Non-vitamin K antagonist oral anticoagulants (NOACs) offer effective therapy without injections or blood monitoring. This bibliometric analysis explores the research on NOACs for preventing VTE and pulmonary embolism.

METHODS: Literature up to July 20, 2024, was searched in Web of Science Core Collection. Citespace software was used for screening and analysis.

RESULTS: In this study, we analyzed 2124 articles and 767 reviews from 11,282 institutions across 528 countries and regions, encompassing 830 publications and 60 research directions. The USA led in publication count, followed by Germany and Canada. Cardiovascular System Cardiology, Hematology, and General Internal Medicine were the top research areas, while THROMBOSIS AND HAEMOSTASIS was the leading journal. From 2004 to 2024, we observed accelerated publication growth, particularly from 2008, highlighting the emergence of NOACs as a major research focus. Key contributors, including Bengt I. Eriksson, and major institutions like Harvard Medical School and University of Amsterdam, played pivotal roles in advancing anticoagulant research. Co-citation and keyword clustering analyses revealed research hotspots in NOACs, cancer-associated venous thromboembolism, stroke prevention, and COVID-19-related thrombotic events, reflecting a shift towards individualized anticoagulation therapy and the growing importance of NOACs in various clinical contexts.

CONCLUSION: The development of NOACs has progressed rapidly, with an increasing number of publications, indicating the lead research in the United States and other Western nations. Comparative studies on the safety and efficacy of NOACs have become a significant focus, shifting from traditional anticoagulants. Pharmacogenetics-guided use of NOACS shows new hope of precision medicine.

PMID:40322032 | PMC:PMC12050026 | DOI:10.2147/DDDT.S505751

Pharmacol Res Perspect. 2025 Jun;13(3):e70103. doi: 10.1002/prp2.70103.

NO ABSTRACT

PMID:40317878 | DOI:10.1002/prp2.70103

Sci Rep. 2025 May 2;15(1):15330. doi: 10.1038/s41598-025-94679-7.

ABSTRACT

The biotransformation of primaquine is mediated by cytochrome P-450 (CYP) enzymes and monoamine oxygenase A (MAO-A). Polymorphisms in the genes that encode these enzymes can alter the clinical response of patients with Plasmodium vivax malaria, leading to therapeutic failure and recurrences. This study aimed to investigate the influence of variations in CYP2D6, MAOA, and UGT2B7 genes on recurrences of vivax malaria. In this case-control study, 72 individuals with vivax malaria were divided into two groups: 18 recurrences and 54 non-recurrences cases. Genotyping of CYP2D6, MAOA, and UGT2B7 was performed using a TaqMan assay and Real-time PCR. The frequency of CYP2D6 alleles was similar between the groups, except for the reduced-function allele *4, which was more frequent in the recurrence group (p = 0.019). Furthermore, the CYP2D6 normal metabolizers (gNM) phenotype had a higher frequency in individuals without recurrence (p = 0.039). An association was found between mutated MAOA genotypes (CC + CT) and a shorter time to recurrence compared to the wild-type (p = 0.0437). However, no association was found between UGT2B7 genotypes and recurrence. These findings suggest that genetic variations in both CYP2D6 and MAOA may contribute to the therapeutic failure of primaquine, reinforcing the importance of pharmacogenetics in monitoring antimalarial therapies.

PMID:40316617 | DOI:10.1038/s41598-025-94679-7

Am J Respir Crit Care Med. 2025 Apr 30. Online ahead of print.

NO ABSTRACT

PMID:40315143

Front Genet. 2025 Apr 17;16:1509042. doi: 10.3389/fgene.2025.1509042. eCollection 2025.

ABSTRACT

OBJECTIVES: This study aims to identify specific single nucleotide polymorphism (SNP) correlated to perioperative analgesia in patients undergoing laparoscopic gynecological surgery.

METHODS: A total of 200 females meeting specific criteria underwent gynecological laparoscopic procedures under general anesthesia. Preoperative pain sensitivity was evaluated using Pain Sensitivity Questionnaire and Pain Catastrophizing Scale (PCS). Venous blood samples were collected for SNP analysis of nine genes. The study analyzed the correlation between SNPs and pre-operative pain assessment, analgesics usage, and the occurrence of related adverse effects.

RESULTS: Six out of nine identified loci showed polymorphisms. The PCS scores were higher in the mutation group (GG + GC) for ADRA2A rs1800544 compared to the CC group (P < 0.05). No differences were observed in visual analog scale or Ramsay sedation scores between the mutation and wild-type groups for any of the SNPs (P < 0.05). Patients in the mutant group (AG + GG) for OPRM1 rs1799971 had higher analgesic usage within 24 h compared to the wild-type group (P < 0.05). The consumption of intraoperative remifentanil was higher in the mutation group (GG + GC) of ADRA2A rs1800544 than in the CC group. The Multifactorial Dimensionality Reduction analysis suggests that the optimal interaction model includes OPRM1 rs179971 and CYP450 3A4 * 1G rs2242480 together.

CONCLUSION: Patients with GG and AG genotypes of OPRM1 rs1799971 gene required more 24-h postoperative analgesics after gynecological surgery compared to those with AA genotype. A SNP-SNP interaction was observed between OPRM1 rs179971 and CYP450 3A4 * 1G rs2242480. Clinical Trial Registration: (www.chictr.org.cn, registration number: ChiCTR2200062425).

PMID:40313598 | PMC:PMC12043472 | DOI:10.3389/fgene.2025.1509042

Children (Basel). 2025 Apr 8;12(4):481. doi: 10.3390/children12040481.

ABSTRACT

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30-40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

PMID:40310132 | DOI:10.3390/children12040481

Am J Respir Cell Mol Biol. 2025 Apr 30. doi: 10.1165/rcmb.2024-0595LE. Online ahead of print.

NO ABSTRACT

PMID:40305670 | DOI:10.1165/rcmb.2024-0595LE

Biomolecules. 2025 Apr 5;15(4):535. doi: 10.3390/biom15040535.

ABSTRACT

Pharmacogenomics is revolutionizing precision medicine by enabling tailored therapeutic strategies based on an individual genetic and molecular profile. Circular RNAs (circRNAs), a distinct subclass of endogenous non-coding RNAs, have recently emerged as key regulators of drug resistance, tumor progression, and therapeutic responses. Their covalently closed circular structure provides exceptional stability and resistance to exonuclease degradation, positioning them as reliable biomarkers and novel therapeutic targets in cancer management. This review provides a comprehensive analysis of the interplay between circRNAs and pharmacogenomics, focusing on their role in modulating drug metabolism, therapeutic efficacy, and toxicity profiles. We examine how circRNA-mediated regulatory networks influence chemotherapy resistance, alter targeted therapy responses, and impact immunotherapy outcomes. Additionally, we discuss emerging experimental tools and bioinformatics techniques for studying circRNAs, including multi-omics integration, machine learning-driven biomarker discovery, and high-throughput sequencing technologies. Beyond their diagnostic potential, circRNAs are being actively explored as therapeutic agents and drug delivery vehicles. Recent advancements in circRNA-based vaccines, engineered CAR-T cells, and synthetic circRNA therapeutics highlight their transformative potential in oncology. Furthermore, we address the challenges of standardization, reproducibility, and clinical translation, emphasizing the need for rigorous biomarker validation and regulatory frameworks to facilitate their integration into clinical practice. By incorporating circRNA profiling into pharmacogenomic strategies, this review underscores a paradigm shift toward highly personalized cancer therapies. circRNAs hold immense potential to overcome drug resistance, enhance treatment efficacy, and optimize patient outcomes, marking a significant advancement in precision oncology.

PMID:40305280 | DOI:10.3390/biom15040535

Andrology. 2025 Apr 30. doi: 10.1111/andr.70053. Online ahead of print.

ABSTRACT

Male factor infertility (MFI) is involved in half of the cases of couple infertility. The follicle-stimulating hormone (FSH) therapy is considered efficient to improve semen parameters and pregnancy rate in patients with idiopathic MFI, following the lesson learned from hypogonadotropic hypogonadism. However, while in patients with hypogonadotropic hypogonadism FSH therapy, in combination with human chorionic gonadotropin (hCG), is a well-established treatment, in patients with MFI the effects of the FSH therapy are variable and unpredictable. The FSH therapy in MFI should be a personalized treatment, tailored on the characteristics of the male patient and the couple. The pivotal aspect is the accurate identification of patients who might benefit from such treatment (responders) from those who might not (nonresponders). To date, selection of patients to be treated is based on history, physical examination, semen analysis, and hormonal assessment. However, these parameters cannot adequately identify a priori responder patients. Furthermore, tailored management should include pharmacological adaptation (dosage and duration of the therapy), as happens during ovarian hyperstimulation in assisted reproductive technologies. In a fully personalized therapy, pharmacogenetic factors must be considered. In this paper, we describe the evidence dealing with the pharmacogenetics of the FSH therapy in MFI, presenting the physiological and physiopathological basis and the pharmacogenetics studies dealing with effects of polymorphisms in the beta-subunit of FSH (FSHB) and the FSH receptor (FSHR) gene. According to the evidence so far available, genetic evaluation of FSHB and FSHR is recommended only for research purposes, since the data are not conclusive and even contrasting. Furthermore, the evidence so far is derived from quite small studies with different endpoints considered and relatively few cases. Better studies that consider the combined effect of several FSHB and FSHR gene polymorphisms, together with clinical, biochemical, seminal and testicular cytology, are necessary to develop an algorithm that might predict the response to the FSH treatment.

PMID:40304702 | DOI:10.1111/andr.70053

Clin Pharmacol Ther. 2025 Apr 30. doi: 10.1002/cpt.3702. Online ahead of print.

ABSTRACT

Older adults (65 years and over) frequently manage complex medication regimens and are vulnerable to adverse drug reactions and treatment inefficacies, some of which could be preventable with pharmacogenetics (PGx)-guided prescribing. This study examined the prevalence of actionable PGx genotypes (i.e., those linked to a guideline that recommends a change to standard prescribing), the use of cautionary medications (i.e., those associated with an actionable PGx genotype), polypharmacy (i.e., ≥ 5 medications simultaneously), and cytochrome P450 enzyme inhibitor and inducer use among 13,670 older adults enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Genotyping was conducted for 10 pharmacogenes with actionable PGx-based prescribing guidelines. Medication data were collected annually and assessed to identify cautionary medication use in the cohort. Most participants (98.8%) carried at least one actionable PGx genotype, with an average of three actionable genotypes per participant. VKORC1 (61.1%) and CYP2C19 (59.6%) were the most frequently observed genes with actionable genotypes. Statins (29.3%), nonsteroidal anti-inflammatory drugs (14.2%), and proton-pump inhibitors (7.9%) were the most used cautionary medications, with 27.5% of participants taking at least one medication for which PGx guidelines recommended a deviation from standard prescribing. Most (83.9%) participants reported taking a polypharmacy regimen, and 68.2% reported use of at least one cytochrome P450 enzyme inhibitor or inducer during the trial. Our findings underscore the high prevalence of actionable PGx genotypes, polypharmacy, and use of inhibitors and inducers in older adults, which collectively have the potential to inform safer and more effective prescribing practices.

PMID:40304392 | DOI:10.1002/cpt.3702

Nat Metab. 2025 Apr 29. doi: 10.1038/s42255-025-01294-x. Online ahead of print.

ABSTRACT

Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.

PMID:40301583 | DOI:10.1038/s42255-025-01294-x

Pac Symp Biocomput. 2025;30:457-472. doi: 10.1142/9789819807024_0033.

ABSTRACT

Adverse drug responses (ADRs) result in over 7,000 deaths annually. Pharmacogenomic studies have shown that many ADRs are partially attributable to genetics. However, emerging data suggest that epigenetic mechanisms, such as DNA methylation (DNAm) also contribute to this variance. Understanding the impact of DNA methylation on drug response may minimize ADRs and improve the personalization of drug regimens. In this work, we identify DNA methylation sites that likely impact drug response phenotypes for anticoagulant and cardiometabolic drugs. We use instrumental variable analysis to integrate genome-wide association study (GWAS) summary statistics derived from electronic health records (EHRs) within the U.K. Biobank (UKBB) with methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). This approach allows us to achieve a robust sample size using the largest publicly available pharmacogenomic GWAS. For warfarin, we find 71 DNAm sites. Of those, 8 are near the gene VKORC1 and 48 are on chromosome 6 near the human leukocyte antigen (HLA) gene family. We also find 2 warfarin DNAm sites near the genes CYP2C9 and CYP2C19. For statins, we identify 17 DNAm sites. Eight are near the APOB gene, which encodes a carrier protein for low-density lipoprotein cholesterol (LDL-C). We find no novel significant epigenetic results for metformin.

PMID:40299609 | DOI:10.1142/9789819807024_0033

Pac Symp Biocomput. 2025;30:229-246. doi: 10.1142/9789819807024_0017.

ABSTRACT

Pharmacogenetics represents one of the most promising areas of precision medicine, with several guidelines for genetics-guided treatment ready for clinical use. Despite this, implementation has been slow, with few health systems incorporating the technology into their standard of care. One major barrier to uptake is the lack of education and awareness of pharmacogenetics among clinicians and patients. The introduction of large language models (LLMs) like GPT-4 has raised the possibility of medical chatbots that deliver timely information to clinicians, patients, and researchers with a simple interface. Although state-of-the-art LLMs have shown impressive performance at advanced tasks like medical licensing exams, in practice they still often provide false information, which is particularly hazardous in a clinical context. To quantify the extent of this issue, we developed a series of automated and expert-scored tests to evaluate the performance of chatbots in answering pharmacogenetics questions from the perspective of clinicians, patients, and researchers. We applied this benchmark to state-of-the-art LLMs and found that newer models like GPT-4o greatly outperform their predecessors, but still fall short of the standards required for clinical use. Our benchmark will be a valuable public resource for subsequent developments in this space as we work towards better clinical AI for pharmacogenetics.

PMID:40299593 | DOI:10.1142/9789819807024_0017

Biomedicines. 2025 Mar 28;13(4):814. doi: 10.3390/biomedicines13040814.

ABSTRACT

Background/Objectives: Activating epidermal growth factor receptor (EGFR) variants is the most common targetable alteration in non-small cell lung cancer (NSCLC). Clinical decision-making requires fast and reliable detection of EGFR variants in early and advanced NSCLC, but limited available tissue necessitates tissue-sparing approaches and optimized sample management. The objective of this study was to assess the performance of the commercial EasyPGX® ready EGFR assay using real-world clinical NSCLC samples. Methods: A consecutive cohort of 804 non-squamous NSCLC samples was prospectively analyzed with the real-time quantitative polymerase chain reaction (RT-qPCR)-based EasyPGX® ready EGFR assay (Diatech Pharmacogenetics, Jesi, Ancona, Italy) and compared to next-generation sequencing (NGS) assays. Results: NGS revealed conclusive results in 99.7% samples, of which 11.1% had at least one EGFR variant. The most common variants were exon 19 deletions and p.L858R. The RT-qPCR-based assay identified EGFR variants with high accuracy (overall concordance rate 94.3%) over a broad range of clinical sample types, variant allele frequencies, tumor cell contents and deoxyribonucleic acid (DNA) input amounts. Conclusions: This study demonstrates that the EasyPGX® ready EGFR assay is a valid approach for the rapid detection of common EGFR variants in real-world clinical NSCLC samples with DNA inputs as low as 5 ng (less than the 15 ng recommended by the manufacturer), improving sample management in small specimens with limited quantity of nucleic acids.

PMID:40299437 | DOI:10.3390/biomedicines13040814

Transl Stroke Res. 2025 Apr 29. doi: 10.1007/s12975-025-01350-4. Online ahead of print.

ABSTRACT

To investigate the association between rs402007 polymorphism in the ADAMTS-1 gene and carotid atherosclerotic plaque vulnerability, as well as the lipid-lowering efficacy of atorvastatin in cerebral infarction patients. Clinical data from 684 cerebral infarction patients admitted to The First Hospital of Hebei Medical University (2016-2019) were analyzed. Patients were stratified into stable plaque (n = 338) and vulnerable plaque (n = 346) groups based on carotid ultrasound. General information, biochemical markers, rs402007 (G/C) genotypes (dominant model), and allele frequencies were compared. Polymorphism genotyping was performed using TaqMan SNP assays (Applied Biosystems) on an ABI 7500 Fast Real-Time PCR system. Logistic regression evaluated plaque vulnerability risk factors and gene-risk factor interactions. Atorvastatin's lipid-lowering efficacy was compared across genotypes. Diabetes prevalence, LDL-C, TC, HCY, and FIB levels differed significantly between groups (P < 0.05). Genotypic distribution analysis revealed a higher frequency of the GG genotype in the stable plaque group (29.59% vs. 21.68%, χ2 = 5.618, P = 0.018). Diabetes, LDL-C, HCY, and FIB were independent risk factors for plaque vulnerability (P < 0.05). A significant interaction between rs402007 polymorphism and LDL-C was observed (P < 0.05). Atorvastatin efficacy rates were 82.29% (GG), 84.27% (GC), and 89.27% (CC), with significant post-treatment lipid improvements in all genotypes (P < 0.05). The CC genotype exhibited superior efficacy compared to GG (P < 0.05). The rs402007 polymorphism influences carotid plaque vulnerability and modulates atorvastatin efficacy, underscoring its potential role in genotype-guided therapeutic strategies.

PMID:40299202 | DOI:10.1007/s12975-025-01350-4

Clin Transl Sci. 2025 May;18(5):e70225. doi: 10.1111/cts.70225.

ABSTRACT

Simvastatin, an HMG-CoA reductase inhibitor, is widely used for hypercholesterolemia but may cause myotoxicity linked to its plasma concentration. Pharmacokinetic gene polymorphisms influence inter-individual variability in simvastatin exposure. This study investigated the effects of pharmacokinetic gene polymorphisms on steady-state simvastatin plasma levels in Thai patients. Eighty-nine Thai patients with dyslipidemia or coronary artery disease on simvastatin treatment for at least 2 weeks without dose adjustment were recruited from King Chulalongkorn Memorial Hospital. Simvastatin lactone and acid concentrations were measured 12 h post-dose using UHPLC-MS/MS. Pharmacokinetic gene polymorphisms, including ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, CYP3A4, and CYP3A5, were genotyped by MassARRAY System. The results showed that patients with the SLCO1B1 c.521TC+CC genotype had significantly higher simvastatin acid levels than those with c.521TT (0.53 vs. 0.19 ng/mL, p = 0.03). Similarly, the SLCO1B1*1b/*15 genotype was associated with higher simvastatin acid levels than SLCO1B1*1a/*1a (0.58 vs. 0.16 ng/mL, p < 0.001). These findings suggest that SLCO1B1 c.521T>C, alone or with c.388A>G (SLCO1B1*1b/*15), reduces OATP1B1 function, leading to elevated simvastatin acid levels and increased myotoxicity risk. This study confirms the association of SLCO1B1 rs4149056 (c.521T>C) with higher simvastatin plasma levels in Thai patients. The study highlights the potential role of SLCO1B1 genotyping, particularly rs4149056 (c.521T>C) and rs2306283 (c.388A>G), in guiding statin therapy for Thai patients, which could help optimize treatment and reduce adverse effects such as statin-induced myotoxicity.

PMID:40297930 | DOI:10.1111/cts.70225

Diabetes Metab Syndr Obes. 2025 Apr 23;18:1255-1262. doi: 10.2147/DMSO.S500336. eCollection 2025.

ABSTRACT

BACKGROUND/OBJECTIVES: This subgroup analysis of a randomised, open-label, two-period crossover trial in Aotearoa New Zealand (February 2019 to March 2020) assessed whether the glucose-lowering effects of vildagliptin, vs pioglitazone varied by the CREBRF (p.Arg457Gln) rs373863828 genotype.

METHODS: Adults with type 2 diabetes and HbA1c > 58 mmol/mol (>7.5%) received either pioglitazone (30 mg) or vildagliptin (50 mg) for 16 weeks, then switched medications for another 16 weeks. Differences in HbA1c between treatments (pioglitazone vs vildagliptin) were tested for an interaction with CREBRF rs373863828 A-allele carrier status and controlling for baseline HbA1c using linear mixed models. Secondary endpoints included weight, systolic blood pressure, and diabetes treatment satisfaction.

RESULTS: Participants with the AA/AG genotype had a higher baseline weight than those with the GG genotype (121.4 kg vs 106.6 kg, respectively; p<0.01). No significant difference in achieved HbA1c was found based on A-allele carrier status (0.43 mmol/mol; 95% CI -4.83, 5.69; p=0.87). Among Māori and Pacific participants with the A-allele, a smaller weight difference was observed after pioglitazone vs vildagliptin compared to those with the GG genotype (interaction effect -1.66 kg; 95% CI -3.27, -0.05; p=0.04).

CONCLUSION: CREBRF rs373863828 A-allele carriers show a similar HbA1c-lowering response to pioglitazone vs vildagliptin compared to non-carriers but exhibit less weight gain with pioglitazone, despite having significantly higher baseline weights.

PMID:40297769 | PMC:PMC12035406 | DOI:10.2147/DMSO.S500336

Front Pharmacol. 2025 Apr 14;16:1524623. doi: 10.3389/fphar.2025.1524623. eCollection 2025.

ABSTRACT

INTRODUCTION: Thyroid cancer, a prevalent endocrine malignancy, has an age-standardized incidence rate of 9.1 per 100,000 people and a mortality rate of 0.44 per 100,000 as of 2024. Despite significant advances in precision oncology driven by large-scale international consortia, gaps persist in understanding the genomic landscape of thyroid cancer and its impact on therapeutic efficacy across diverse populations.

METHODS: To address this gap, we performed comprehensive data mining and in silico analyses to identify pathogenic variants in thyroid cancer driver genes, calculate allele frequencies, and assess deleteriousness scores across global populations, including African, Amish, Ashkenazi Jewish, East and South Asian, Finnish and non-Finnish European, Latino, and Middle Eastern groups. Additionally, pharmacogenomic profiling, in silico drug prescription, and clinical trial data were analyzed to prioritize targeted therapeutic strategies.

RESULTS: Our analysis examined 56,622 variants in 40 thyroid cancer-driver genes across 76,156 human genomes, identifying 5,001 known and predicted oncogenic variants. Enrichment analysis revealed critical pathways such as MAPK, PI3K-AKT-mTOR, and p53 signaling, underscoring their roles in thyroid cancer pathogenesis. High-throughput validation strategies confirmed actionable genomic alterations in RET, BRAF, NRAS, KRAS, and EPHA7. Ligandability assessments identified these proteins as promising therapeutic targets. Furthermore, our findings highlight the clinical potential of targeted drug inhibitors, including vandetanib, dabrafenib, and selumetinib, for improving treatment outcomes.

DISCUSSION: This study underscores the significance of integrating genomic insights with pharmacogenomic strategies to address disparities in thyroid cancer treatment. The identification of population-specific oncogenic variants and actionable therapeutic targets provides a foundation for advancing precision oncology. Future efforts should focus on including underrepresented populations, developing population-specific prevention strategies, and fostering global collaboration to ensure equitable access to pharmacogenomic testing and innovative therapies. These initiatives have the potential to transform thyroid cancer care and align with the broader goals of personalized medicine.

PMID:40297138 | PMC:PMC12034932 | DOI:10.3389/fphar.2025.1524623