Transl Clin Pharmacol. 2024 Jun;32(2):73-82. doi: 10.12793/tcp.2024.32.e8. Epub 2024 May 29.

ABSTRACT

Large language models (LLMs) have emerged as a powerful tool for biomedical researchers, demonstrating remarkable capabilities in understanding and generating human-like text. ChatGPT with its Code Interpreter functionality, an LLM connected with the ability to write and execute code, streamlines data analysis workflows by enabling natural language interactions. Using materials from a previously published tutorial, similar analyses can be performed through conversational interactions with the chatbot, covering data loading and exploration, model development and comparison, permutation feature importance, partial dependence plots, and additional analyses and recommendations. The findings highlight the significant potential of LLMs in assisting researchers with data analysis tasks, allowing them to focus on higher-level aspects of their work. However, there are limitations and potential concerns associated with the use of LLMs, such as the importance of critical thinking, privacy, security, and equitable access to these tools. As LLMs continue to improve and integrate with available tools, data science may experience a transformation similar to the shift from manual to automatic transmission in driving. The advancements in LLMs call for considering the future directions of data science and its education, ensuring that the benefits of these powerful tools are utilized with proper human supervision and responsibility.

PMID:38974344 | PMC:PMC11224898 | DOI:10.12793/tcp.2024.32.e8

Transl Clin Pharmacol. 2024 Jun;32(2):98-106. doi: 10.12793/tcp.2024.32.e9. Epub 2024 Jun 26.

ABSTRACT

Tegoprazan orally disintegrating tablet (ODT) formulation is a novel formulation to improve a convenience in comparison to taking the conventional tablet of tegoprazan, a potassium-competitive acid blocker. The purpose of this study was to evaluate the pharmacokinetic and safety profiles of tegoprazan ODT when administered via two routes: nasogastric tube or oral dosing. This study is expected to expand the administration route of tegoprazan ODT. The study was conducted in an open-label, randomized, single-dose, two-way crossover design with a 1-week washout period. Healthy subjects aged 19 to 45 years were administered 50 mg of tegoprazan ODT orally or dissolved in water via nasogastric tube. Tegoprazan, the active ingredient, was quantified using a ultra-high performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and pharmacokinetic parameters were determined through non-compartmental analysis. Safety was monitored throughout the study. A total of 48 subjects, successfully completed the trial. The geometric mean ratios for log-transformed Cmax and AUCt, representing the ratio of nasogastric tube group to oral dosing group, along with 90% confidence intervals, were 1.1087 (1.0243-1.2000) and 1.0023 (0.9620-1.0442), respectively. All adverse events were unrelated to tegoprazan and mild in intensity. The pharmacokinetic profiles of tegoprazan ODT were equivalent between the nasogastric tube and oral administration. Considering the demonstrated linear pharmacokinetics and concentration-dependent pharmacodynamics of tegoprazan, the administration via nasogastric tube is expected to yield effects equivalent to those of oral administration. This approach offers a viable alternative, especially beneficial for patients with oral intake difficulties.

PMID:38974342 | PMC:PMC11224899 | DOI:10.12793/tcp.2024.32.e9

Mol Genet Genomics. 2024 Jul 7;299(1):65. doi: 10.1007/s00438-024-02158-x.

ABSTRACT

BACKGROUND: A large number of challenging medically relevant genes (CMRGs) are situated in complex or highly repetitive regions of the human genome, hindering comprehensive characterization of genetic variants using next-generation sequencing technologies. In this study, we employed long-read sequencing technology, extensively utilized in studying complex genomic regions, to characterize genetic alterations, including short variants (single nucleotide variants and short insertions and deletions) and copy number variations, in 370 CMRGs across 41 individuals from 19 global populations.

RESULTS: Our analysis revealed high levels of genetic variants in CMRGs, with 68.73% exhibiting copy number variations and 65.20% containing short variants that may disrupt protein function across individuals. Such variants can influence pharmacogenomics, genetic disease susceptibility, and other clinical outcomes. We observed significant differences in CMRG variation across populations, with individuals of African ancestry harboring the highest number of copy number variants and short variants compared to samples from other continents. Notably, 15.79% to 33.96% of short variants were exclusively detectable through long-read sequencing. While the T2T-CHM13 reference genome significantly improved the assembly of CMRG regions, thereby facilitating variant detection in these regions, some regions still lacked resolution.

CONCLUSION: Our results provide an important reference for future clinical and pharmacogenetic studies, highlighting the need for a comprehensive representation of global genetic diversity in the reference genome and improved variant calling techniques to fully resolve medically relevant genes.

PMID:38972030 | DOI:10.1007/s00438-024-02158-x

J Genet Genomics. 2024 Jul 3:S1673-8527(24)00161-9. doi: 10.1016/j.jgg.2024.06.018. Online ahead of print.

ABSTRACT

Human UDP-glycosyltransferases (UGTs) are responsible for the glucuronidation of a wide variety of endogenous substrates and multiple commonly prescribed drugs. Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk. However, the genetic complexity beyond these variants has not been comprehensively assessed. We here leveraged whole-exome and whole-genome sequencing data from 141,456 unrelated individuals across seven major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family. Overall, 9666 exonic variants were observed of which 98.9% were rare. To interpret the functional impact of UGT missense variants, we developed a gene family-specific variant effect predictor. This algorithm identified a total of 1208 deleterious variants, most of which were found in African and South Asian populations. Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites. Combined, our analyses provide a systematic overview of UGT variability, which can yield insights into inter-individual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.

PMID:38969258 | DOI:10.1016/j.jgg.2024.06.018

J Ethnopharmacol. 2024 Jul 3:118523. doi: 10.1016/j.jep.2024.118523. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: HLA-B*35:01 has been identified as a risk allele for Polygonum multiflorum Thunb.-induced liver injury (PMLI). However, the immune mechanism underlying HLA-B*35:01-mediated PMLI remains unknown.

AIM OF THE STUDY: To characterize the immune mechanism of HLA-B*35:01-mediated PMLI.

MATERIALS AND METHODS: Components of P. multiflorum (PM) bound to the HLA-B*35:01 molecule was screened by immunoaffinity chromatography. Both wild-type mice and HLA-B*35:01 transgenic (TG) mice were treated with emodin. The levels of transaminases, histological changes and T-cell response were assessed. Splenocytes from emodin-treated mice were isolated and cultured in vitro. Phenotypes and functions of T cells were characterized upon drug restimulation using flow cytometry or ELISA. Emodin-pulsed antigen-presenting cells (APCs) or glutaraldehyde-fixed APCs were co-cultured with splenocytes from emodin-treated transgenic mice to detect their effect on T-cell activation.

RESULTS: Emodin, the main component of PM, could non-covalently bind to the HLA-B*35:01-peptide complexes. TG mice were more sensitive to emodin-induced immune hepatic injury, as manifested by elevated aminotransferase levels, infiltration of inflammatory cells, increased percentage of CD8+T cells and release of effector molecules in the liver. However, these effects were not observed in wild-type mice. An increase in percentage of T cells and the levels of interferon-γ, granzyme B, and perforin was detected in emodin-restimulated splenocytes from TG mice. Anti-HLA-I antibodies inhibited the secretion of these effector molecules induced by emodin. Mechanistically, emodin-pulsed APCs failed to stimulate T cells, while fixed APCs in the presence of emodin could elicit the secretion of T cell effector molecules.

CONCLUSION: The HLA-B*35:01-mediated CD8+ T cell reaction to emodin through the P-I mechanism may contribute to P. multiflorum-induced liver injury.

PMID:38969149 | DOI:10.1016/j.jep.2024.118523

Adv Pharmacol Pharm Sci. 2024 Jun 27;2024:4862706. doi: 10.1155/2024/4862706. eCollection 2024.

ABSTRACT

Cyclophosphamide (Cy) is a prodrug that is mainly bioactivated by cytochrome P450 (CYP) 2B6 enzyme. Several other enzymes are also involved in its bioactivation and affect its kinetics. Previous studies have shown the effect of the enzymes' genetic polymorphisms on Cy kinetics and its clinical outcome. These results were controversial primarily because of the involvement of several interacting enzymes in the Cy metabolic pathway, which can also be affected by several clinical factors as well as other drug interactions. In this review article, we present the effect of CYP2B6 polymorphisms on Cy kinetics since it is the main bioactivating enzyme, as well as discussing all previously reported enzymes and clinical factors that can alter Cy efficacy. Additionally, we present explanations for key Cy side effects related to the nature and site of its bioactivation. Finally, we discuss the role of busulphan in conditioning regimens in the Cy metabolic pathway as a clinical example of drug-drug interactions involving several enzymes. By the end of this article, our aim is to have provided a comprehensive summary of Cy pharmacogenomics and the effect on its kinetics. The utility of these findings in the development of new strategies for Cy personalized patient dose adjustment will aid in the future optimization of patient specific Cy dosages and ultimately in improving clinical outcomes. In conclusion, CYP2B6 and several other enzyme polymorphisms can alter Cy kinetics and consequently the clinical outcomes. However, the precise quantification of Cy kinetics in any individual patient is complex as it is clearly under multifactorial genetic control. Additionally, other clinical factors such as the patient's age, diagnosis, concomitant medications, and clinical status should also be considered.

PMID:38966316 | PMC:PMC11223907 | DOI:10.1155/2024/4862706

Breast Cancer Res. 2024 Jul 4;26(1):111. doi: 10.1186/s13058-024-01861-2.

ABSTRACT

BACKGROUND: Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies.

METHODS: We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog.

RESULTS: We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs.

CONCLUSIONS: We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.

PMID:38965614 | DOI:10.1186/s13058-024-01861-2

Endocrinology. 2024 Jul 4:bqae077. doi: 10.1210/endocr/bqae077. Online ahead of print.

ABSTRACT

Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes, however, is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation and liver necrosis/cell death. Together these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.

PMID:38963813 | DOI:10.1210/endocr/bqae077

Eur J Clin Pharmacol. 2024 Jul 4. doi: 10.1007/s00228-024-03721-6. Online ahead of print.

ABSTRACT

PURPOSE: The CYP2D6 gene exhibits significant polymorphism, contributing to variability in responses to drugs metabolized by CYP2D6. While CYP2D6*2 and CYP2D6*35 are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called "enhancer" single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of CYP2D6*2, CYP2D6*35 and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker.

METHODS: A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed CYP2D6 allele or haplotype. In addition to the well-characterized CYP2D6 alleles (*3-*6, *9, *10 and *41), *2, *35 and two haplotypes assigned as CYP2D6*2-rs5758550G and CYP2D6*2-rs5758550A were evaluated.

RESULTS: Each evaluated CYP2D6 allele was associated with significantly lower risperidone clearance than the reference normal function allele CYP2D6*1 (p < 0.001). Further, rs5758550 differentiated the effect of CYP2D6*2 (p = 0.005). The haplotype-specific clearances for CYP2D6*2-rs5758550A, CYP2D6*2-rs5758550G and CYP2D6*35 were estimated to 30%, 66% and 57%, respectively, relative to the clearance for CYP2D6*1. Notably, rs5758550 is in high linkage disequilibrium (R2 > 0.85) with at least 24 other SNPs and cannot be assigned as a functional SNP.

CONCLUSION: CYP2D6*2 and CYP2D6*35 encode reduced risperidone clearance, and the extent of reduction for CYP2D6*2 is differentiated by rs5758550. Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance.

PMID:38963454 | DOI:10.1007/s00228-024-03721-6

Intern Med J. 2024 Jul 4. doi: 10.1111/imj.16463. Online ahead of print.

ABSTRACT

BACKGROUND: Despite common global usage, fluoropyrimidine (FP; 5-flurouracil and capecitabine)-related chemotherapy toxicity is poorly reported in the literature, with serious toxicity ranging from 10% to 40% and early toxicity (within 60 days of exposure) quoted at 14%. Data reflecting the incidence of Grades 3-5 FP-related toxicity in Australian cancer patients is scant, despite the significant impact of toxicity on patients (hospitalisations, intensive care unit (ICU) admissions and even death).

AIMS: This retrospective audit evaluated Grades 3-5 toxicities in a contemporaneous cohort of 500 patients receiving FP chemotherapies within the Hunter-New England Local Health District from June 2020 to June 2022. Data were extracted from public hospital records and oncology-specific e-records to determine rates of toxicity and associated hospitalisations, intensive care admissions and deaths that occurred within 60 days of first exposure to FP chemotherapy-containing regimens.

RESULTS: One hundred and fifty incidents of Grades 3-4 toxicity in the first 60 days led to 87 patients presenting to hospital (87/500, 17.4%). The most common serious toxicities were diarrhoea (39.3%), nausea and vomiting (22.7%) and febrile neutropaenia (10%). Four patients were admitted to the ICU, and four patients died of toxicity. Within the first 60 days, 22.2% of patients required treatment delays, 21.4% required dose reductions, and 7.8% of patients ceased treatment because of toxicities.

DISCUSSION AND CONCLUSION: Our experience reflects international reports and is likely generalisable to the Australian population. These data are a basis to understand the potential benefits of precision medicine strategies such as pharmacogenomic screening to improve patient tolerability and the cost-effectiveness of FP chemotherapy prescribing.

PMID:38963005 | DOI:10.1111/imj.16463

Afr Health Sci. 2024 Mar;24(1):307-312. doi: 10.4314/ahs.v24i1.36.

ABSTRACT

INTRODUCTION: Pharmacogenetic markers, such as the ATP Binding Cassette (ABCB1) and cytochrome P450 (CYP) 3A5 enzymes, play a crucial role in personalized medicine by influencing drug efficacy and toxicity based on individuals' or populations' genetic variations.This study aims to investigate the genetic polymorphisms of CYP3A5 (rs776746) and ABCB1 (rs1045642) in the West Algerian population and compare the genotypes and allelic distributions with those of various ethnic groups.

METHODS: The study involved 472 unrelated healthy subjects from the Western Algerian population. DNA genotyping was performed using TaqMan allelic discrimination assay. The variants in our population were compared to those in other ethnic groups available in the 1000 Genomes Project. Genotype and allele frequencies were calculated using the chi-square test and the Hardy-Weinberg equilibrium (HWE).

RESULTS: The minor allele frequencies were found to be 0.21 for CYP3A5 6986A and 0.34 for ABCB1 3435T. These frequencies were similar to those observed in North African populations, while notable differences were observed in comparison to certain Caucasian and African populations.

CONCLUSION: The difference in the allelic and genotypic distribution of these polymorphisms emphasize the need for dose adjustments in drugs metabolized by CYP3A5 and transported by ABCB1 to optimize treatments outcomes.

PMID:38962329 | PMC:PMC11217850 | DOI:10.4314/ahs.v24i1.36

Eur J Pharm Sci. 2024 Jul 1:106838. doi: 10.1016/j.ejps.2024.106838. Online ahead of print.

ABSTRACT

Physiologically based pharmacokinetic (PBPK) models which can leverage preclinical data to predict the pharmacokinetic properties of drugs rapidly became an essential tool to improve the efficiency and quality of novel drug development. In this review, by searching the Application Review Files in Drugs@FDA, we analyzed the current application of PBPK models in novel drugs approved by the U.S. Food and Drug Administration (FDA) in the past five years. According to the results, 243 novel drugs were approved by the FDA from 2019 to 2023. During this period, 74 Application Review Files of novel drugs approved by the FDA that used PBPK models. PBPK models were used in various areas, including drug-drug interactions (DDI), organ impairment (OI) patients, pediatrics, drug-gene interaction (DGI), disease impact, and food effects. DDI was the most widely used area of PBPK models for novel drugs, accounting for 74.2% of the total. Software platforms with graphical user interfaces (GUI) have reduced the difficulty of PBPK modeling, and Simcyp was the most popular software platform among applicants, with a usage rate of 80.5%. Despite its challenges, PBPK has demonstrated its potential in novel drug development, and a growing number of successful cases provide experience learned for researchers in the industry.

PMID:38960205 | DOI:10.1016/j.ejps.2024.106838

Sci Rep. 2024 Jul 3;14(1):15312. doi: 10.1038/s41598-024-66113-x.

ABSTRACT

Nontuberculous mycobacteria (NTM) infection diagnosis remains a challenge due to its overlapping clinical symptoms with tuberculosis (TB), leading to inappropriate treatment. Herein, we employed noninvasive metabolic phenotyping coupled with comprehensive statistical modeling to discover potential biomarkers for the differential diagnosis of NTM infection versus TB. Urine samples from 19 NTM and 35 TB patients were collected, and untargeted metabolomics was performed using rapid liquid chromatography-mass spectrometry. The urine metabolome was analyzed using a combination of univariate and multivariate statistical approaches, incorporating machine learning. Univariate analysis revealed significant alterations in amino acids, especially tryptophan metabolism, in NTM infection compared to TB. Specifically, NTM infection was associated with upregulated levels of methionine but downregulated levels of glutarate, valine, 3-hydroxyanthranilate, and tryptophan. Five machine learning models were used to classify NTM and TB. Notably, the random forest model demonstrated excellent performance [area under the receiver operating characteristic (ROC) curve greater than 0.8] in distinguishing NTM from TB. Six potential biomarkers for NTM infection diagnosis, including methionine, valine, glutarate, 3-hydroxyanthranilate, corticosterone, and indole-3-carboxyaldehyde, were revealed from univariate ROC analysis and machine learning models. Altogether, our study suggested new noninvasive biomarkers and laid a foundation for applying machine learning to NTM differential diagnosis.

PMID:38961191 | DOI:10.1038/s41598-024-66113-x

Cancer Res. 2024 Jul 3. doi: 10.1158/0008-5472.CAN-23-3594. Online ahead of print.

ABSTRACT

Substantial heterogeneity in molecular features, patient prognoses, and therapeutic responses in head and neck squamous cell carcinomas (HNSCC) highlights the urgent need to develop molecular classifications that reliably and accurately reflect tumor behavior and inform personalized therapy. Here, we leveraged the similarity network fusion bioinformatics approach to jointly analyze multi-omics datasets spanning copy number variations, somatic mutations, DNA methylation, and transcriptomic profiling and derived a prognostic classification system for HNSCC. The integrative model consistently identified three subgroups (IMC1-3) with specific genomic features, biological characteristics, and clinical outcomes across multiple independent cohorts. The IMC1 subgroup included proliferative, immune-activated tumors and exhibited a more favorable prognosis. The IMC2 subtype harbored activated EGFR signaling and an inflamed tumor microenvironment with cancer-associated fibroblast/vascular infiltrations. Alternatively, the IMC3 group featured highly aberrant metabolic activities and impaired immune infiltration and recruiting. Pharmacogenomics analyses from in silico predictions and from patient-derived xenograft model data unveiled subtype-specific therapeutic vulnerabilities including sensitivity to cisplatin and immunotherapy in IMC1 and EGFR inhibitors (EGFRi) in IMC2, which was experimentally validated in patient-derived organoid models. Two signatures for prognosis and EGFRi sensitivity were developed via machine learning. Together, this integrative multi-omics clustering for HNSCC improves current understanding of tumor heterogeneity and facilitates patient stratification and therapeutic development tailored to molecular vulnerabilities.

PMID:38959352 | DOI:10.1158/0008-5472.CAN-23-3594

Braz J Med Biol Res. 2024 Jul 1;57:e13257. doi: 10.1590/1414-431X2024e13257. eCollection 2024.

ABSTRACT

Rivaroxaban is a direct factor Xa inhibitor. Its interindividual variability is large and may be connected to the occurrence of adverse drug reactions or drug inefficacy. Pharmacogenetics studies concentrating on the reasons underlying rivaroxaban's inadequate response could help explain the differences in treatment results and medication safety profiles. Against this background, this study evaluated whether polymorphisms in the gene encoding the ABCG2 transporter modify the pharmacokinetic characteristics of rivaroxaban. A total of 117 healthy volunteers participated in two bioequivalence experiments with a single oral dose of 20 mg rivaroxaban, with one group fasting and the other being fed. Ultra-high-performance liquid chromatography coupled with mass spectrometry was employed to determine the plasma concentrations of rivaroxaban, and the WinNonlin program was used to calculate the pharmacokinetics parameters. In the fasting group, the rivaroxaban pharmacokinetic parameters of Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) were significantly higher in ABCG2 421 A/A genotype carriers than in ABCG2 421 C/C and 421 C/A genotype carriers (P<0.05). The mean values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL·h), and Cl (11.82 vs 14.50 vs 13.01 mL/h) for these groups were lower, but this difference was not statistically significant (P>0.05). These findings suggested that the ABCG2 421 A/A genotype may impact rivaroxaban parameters after a single dose in healthy subjects. This finding must be validated before it is applied in clinical practice.

PMID:38958362 | DOI:10.1590/1414-431X2024e13257

Aust J Gen Pract. 2024 Jul;53(7):463-470. doi: 10.31128/AJGP-10-23-6986.

ABSTRACT

BACKGROUND: Cardiovascular diseases (CVDs) pose significant global health challenges, with genetics increasingly recognised as a key factor alongside traditional risk factors. This presents an opportunity for general practitioners (GPs) to refine their approaches.

OBJECTIVE: This article explores the impact of genetics on CVDs and its implications for GPs. It discusses monogenic disorders like inherited cardiomyopathies and polygenic risks, as well as pharmacogenetics, aiming to enhance risk assessment and personalised care.

DISCUSSION: Monogenic disorders, driven by single gene mutations, exhibit predictable inheritance patterns, including inherited cardiomyopathies and channelopathies such as Long QT syndrome. Polygenic risks involve multiple genetic variants influencing CVD susceptibility, addressed through polygenic risk scores for precise risk assessment. Pharmacogenetics tailor drug interventions based on genetic profiles, though challenges like accessibility and ethical considerations persist. Integrating genetics into cardiovascular care holds promise for alleviating the global CVD burden and improving patient outcomes.

PMID:38957060 | DOI:10.31128/AJGP-10-23-6986

Eur J Hum Genet. 2024 Jul 2. doi: 10.1038/s41431-024-01648-1. Online ahead of print.

ABSTRACT

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.

PMID:38956296 | DOI:10.1038/s41431-024-01648-1

Indian J Public Health. 2024 Apr 1;68(2):314-317. doi: 10.4103/ijph.ijph_809_23. Epub 2024 Jun 29.

ABSTRACT

Cancer patients suffer from complicated chemotoxicity. Pharmacogenomics can help stratify patients by predicting their response to treatment and susceptibility toward severe side effects. The spindle-assembly checkpoint (SAC) is an important pathway that is activated by platinum and taxane compounds and plays a crucial role in their cytotoxic activity. This study investigated a SAC component, Budding Uninhibited by Benzimidazoles 3 (BUB3), its expression, and genetic variants in advanced ovarian cancer patients treated with paclitaxel-carboplatin chemotherapy. Among 80 patients, BUB3 expression correlated with chemosensitivity, suggesting its potential as a predictive marker for chemotherapy response. However, high BUB3 expression was associated with a higher risk of poor survival. In addition, genetic polymorphisms in BUB3 (rs11248416 and rs11248419) were significantly linked to chemotherapy-related toxicities, with rs11248416 showing a negative impact on the patient's physical quality of life.

PMID:38953826 | DOI:10.4103/ijph.ijph_809_23

Clin Pharmacol Ther. 2024 Jul 1. doi: 10.1002/cpt.3351. Online ahead of print.

ABSTRACT

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).

PMID:38951961 | DOI:10.1002/cpt.3351

Pharmacogenomics J. 2024 Jun 29;24(4):21. doi: 10.1038/s41397-024-00343-0.

ABSTRACT

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

PMID:38951505 | DOI:10.1038/s41397-024-00343-0