Brief Bioinform. 2024 May 23;25(4):bbae156. doi: 10.1093/bib/bbae156.

ABSTRACT

The development of deep learning models plays a crucial role in advancing precision medicine. These models enable personalized medical treatments and interventions based on the unique genetic, environmental and lifestyle factors of individual patients, and the promotion of precision medicine is achieved mainly through genomic data analysis, variant annotation and interpretation, pharmacogenomics research, biomarker discovery, disease typing, clinical decision support and disease mechanism interpretation. Extensive research has been conducted to address precision medicine challenges using attention mechanism models such as SAN, GAT and transformers. Especially, the recent popularity of ChatGPT has significantly propelled the application of this model type to a new height. Therefore, I propose a Special Issue for Briefings in Bioinformatics about the topic 'Attention Mechanism Models for Precision Medicine'. This Special Issue aims to provide a comprehensive overview and presentation of innovative researches on the application of graph attention mechanism models in precision medicine.

PMID:38811359 | DOI:10.1093/bib/bbae156

Expert Opin Drug Metab Toxicol. 2024 May 29. doi: 10.1080/17425255.2024.2362184. Online ahead of print.

ABSTRACT

INTRODUCTION: In addition to the well-established understanding of the pharmacogenetics of drug metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited.

AREAS COVERED: This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol.

EXPERT OPINION: Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.

PMID:38809523 | DOI:10.1080/17425255.2024.2362184

Cardiovasc Drugs Ther. 2024 May 29. doi: 10.1007/s10557-024-07580-2. Online ahead of print.

ABSTRACT

PURPOSE: Hepatotoxicity has emerged as a major cause of statin treatment interruption. Although organic anion-transporting polypeptide 1B1 (SLCO1B1), multidrug resistance protein 1 (ABCB1), and breast cancer resistance protein (ABCG2) have been identified as transporters of statins, knowledge of their role in statin-associated hepatotoxicity remains limited. Therefore, we aimed to conduct a comprehensive analysis to elucidate the association between hepatotoxicity and SLCO1B1, ABCB1, and ABCG2 polymorphisms.

METHODS: This study retrospectively analyzed prospectively collected samples. We selected 10 single nucleotide polymorphisms (SNPs) of SLCO1B1, 9 SNPs of ABCB1, and 12 SNPs of ABCG2. We developed two models for multivariable analyses (Model I: clinical factors only; Model II: both clinical and genetic factors), and the attributable risk (%) of variables in Model II was determined.

RESULTS: Among 851 patients, 66 (7.8%) developed hepatotoxicity. In Model I, lipophilic statins, atrial fibrillation (Afib), and diabetes mellitus showed a significant association with hepatotoxicity. In Model II, lipophilic statins and Afib, SLCO1B1 rs11045818 A allele, SLCO1B1 rs4149035 T allele, and ABCG2 rs2622629 TT genotype were associated with higher hepatotoxicity risk. Among them, the SLCO1B1 rs11045818 A allele exhibited the highest attributable risk (93.2%). The area under the receiver operating characteristic curve in Model I was 0.62 (95% CI: 0.55-0.69), and it was increased to 0.71 in Model II (95% CI: 0.64-0.77).

CONCLUSION: This study investigated the correlation between hepatotoxicity and polymorphisms of transporter genes in patients taking statins. The findings could help improve personalized treatments for patients receiving statin therapy.

PMID:38809397 | DOI:10.1007/s10557-024-07580-2

J Gastrointest Cancer. 2024 May 29. doi: 10.1007/s12029-024-01071-1. Online ahead of print.

ABSTRACT

The prognostic significance of positive peritoneal cytology still varied between cancer types and geographical origin. However, because of the lack of sensitivity of this biomarker, conventional cytology is not routinely performed in every country. Here, we wanted to test a new biomarker, peritoneal tumour DNA, using NGS technique, in order to compare it with the historical one, in patients having peritoneal metastases of gastrointestinal or ovarian cancer.

PMID:38809368 | DOI:10.1007/s12029-024-01071-1

Expert Opin Drug Metab Toxicol. 2024 May 29. doi: 10.1080/17425255.2024.2362190. Online ahead of print.

NO ABSTRACT

PMID:38809019 | DOI:10.1080/17425255.2024.2362190

Elife. 2024 May 29;12:RP92511. doi: 10.7554/eLife.92511.

ABSTRACT

Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the 'Warburg effect', thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.

PMID:38808578 | DOI:10.7554/eLife.92511

Int J Biochem Cell Biol. 2024 May 26:106600. doi: 10.1016/j.biocel.2024.106600. Online ahead of print.

ABSTRACT

Extracellular vesicles (EVs) represent a heterogeneous group of particles secreted by cells to transfer information from the cell of origin to recipient cells by carrying various bioactive molecules. Numerous PubMed records on EVs reveal a burgeoning interest in EV-research, with a notable subset focusing on the potential diagnostic and therapeutic applications of EVs for diverse diseases, including cardiovascular disease (CVD), currently a globally leading cause of mortality. However, this great diagnostic and clinical potential has not yet been translated into clinical practice. No EV-based biomarkers and EV-therapeutic products have been approved, and EV-based therapy for CVD has not yet been shown to be effective. Therefore, this paper aims to scrutinize available data and identify what is needed to translate the underlying potential of EVs into specific EV-biomarkers and EV-therapeutic tools applicable in clinical practice.

PMID:38806094 | DOI:10.1016/j.biocel.2024.106600

Circ Genom Precis Med. 2024 May 28:e004320. doi: 10.1161/CIRCGEN.123.004320. Online ahead of print.

ABSTRACT

BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).

METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.

RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicates NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicates SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.

CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

PMID:38804128 | DOI:10.1161/CIRCGEN.123.004320

Indian J Pediatr. 2024 May 28. doi: 10.1007/s12098-024-05135-9. Online ahead of print.

ABSTRACT

OBJECTIVES: To conduct a thorough pharmacokinetic (PK) - pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB).

METHODS: Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software.

RESULTS: A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population.

CONCLUSIONS: The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.

PMID:38802673 | DOI:10.1007/s12098-024-05135-9

Eur J Hum Genet. 2024 May 27. doi: 10.1038/s41431-024-01616-9. Online ahead of print.

ABSTRACT

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents' sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

PMID:38802530 | DOI:10.1038/s41431-024-01616-9

Pharmacogenomics J. 2024 May 27;24(3):17. doi: 10.1038/s41397-024-00338-x.

ABSTRACT

Lack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20-30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.

PMID:38802404 | DOI:10.1038/s41397-024-00338-x

Cell Mol Neurobiol. 2024 May 27;44(1):47. doi: 10.1007/s10571-024-01466-5.

ABSTRACT

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

PMID:38801645 | DOI:10.1007/s10571-024-01466-5

J Vis Exp. 2024 May 10;(207). doi: 10.3791/66058.

ABSTRACT

Gastric cancer is a common heterogeneous tumor. Most patients have advanced gastric cancer at the time of diagnosis and often need chemotherapy. Although 5-fluorouracil (5-FU) is widely used for treatment, its therapeutic sensitivity and drug tolerance still need to be determined, which emphasizes the importance of individualized administration. Pharmacogenetics can guide the clinical implementation of individualized treatment. Single nucleotide polymorphisms (SNPs), as a genetic marker, contribute to the selection of appropriate chemotherapy regimens and dosages. Some SNPs are associated with folate metabolism, the therapeutic target of 5-FU. Methylenetetrahydrofolate reductase (MTHFR) rs1801131 and rs1801133, dihydrofolate reductase (DHFR) rs1650697 and rs442767, methionine synthase (MTR) rs1805087, gamma-glutamyl hydrolase (GGH) rs11545078 and solute carrier family 19 member 1 (SLC19A1) rs1051298 have been investigated in different kinds of cancers and antifolate antitumor drugs, which have potential forecasting and guiding significance for application of 5-FU. The ion torrent next-generation semiconductor sequencing technology can rapidly detect gastric cancer-related SNPs. Each time a base is extended in a DNA chain, an H+ will be released, causing local pH changes. The ionic sensor detects pH changes and converts chemical signals into digital signals, achieving sequencing by synthesis. This technique has low sample requirement, simple operation, low cost, and fast sequencing speed, which is beneficial for guiding individualized chemotherapy by SNPs.

PMID:38801272 | DOI:10.3791/66058

Ther Adv Cardiovasc Dis. 2024 Jan-Dec;18:17539447241249886. doi: 10.1177/17539447241249886.

ABSTRACT

Atrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that have been proven to prevent stroke in patients with non-valvular AF. This review summarizes the pharmacokinetics, pharmacodynamics, and drug interactions of DOACs, as well as new data from pharmacogenetic studies of these drugs. This review is aimed at analyzing the scientific literature on the gene polymorphisms involved in the metabolism of DOACs. We searched PubMed, Cochrane, Google Scholar, and CyberLeninka (Russian version) databases with keywords: 'dabigatran', 'apixaban', 'rivaroxaban', 'edoxaban', 'gene polymorphism', 'pharmacogenetics', 'ABCB1', 'CES1', 'SULT1A', 'ABCG2', and 'CYP3A4'. The articles referred for this review include (1) full-text articles; (2) study design with meta-analysis, an observational study in patients taking DOAC; and (3) data on the single-nucleotide polymorphisms and kinetic parameters of DOACs (plasma concentration), or a particular clinical outcome, published in English and Russian languages during the last 10 years. The ages of the patients ranged from 18 to 75 years. Out of 114 reviewed works, 24 were found eligible. As per the available pharmacogenomic data, polymorphisms affecting DOACs are different. This may aid in developing individual approaches to optimize DOAC pharmacotherapy to reduce the risk of hemorrhagic complications. However, large-scale population studies are required to determine the dosage of the new oral anticoagulants based on genotyping. Information on the genetic effects is limited owing to the lack of large-scale studies. Uncovering the mechanisms of the genetic basis of sensitivity to DOACs helps in developing personalized therapy based on patient-specific genetic variants and improves the efficacy and safety of DOACs in the general population.

PMID:38801157 | DOI:10.1177/17539447241249886

Front Immunol. 2024 May 10;15:1369531. doi: 10.3389/fimmu.2024.1369531. eCollection 2024.

ABSTRACT

BACKGROUND: Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.

CASE PRESENTATION: We report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.

CONCLUSION: Efficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.

PMID:38799429 | PMC:PMC11117064 | DOI:10.3389/fimmu.2024.1369531

Clin Pharmacol Ther. 2024 May 26. doi: 10.1002/cpt.3314. Online ahead of print.

ABSTRACT

Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6-dependent opioids while on CYP2D6-inhibitor antidepressants vs. antidepressants that do not inhibit CYP2D6. This retrospective cohort study included adult patients prescribed CYP2D6-dependent opioids utilizing electronic health records data from the University of Florida Health (2015-2021). The association between ED visits and inhibitor exposure was tested using multivariable logistic regression. The primary analysis had 12,118 patients (72% female; mean (SD) age, 55 (13.4)) in the hydrocodone/tramadol/codeine cohort and 5,547 patients (64% female; mean (SD) age, 53.6 (14.2)) in the oxycodone cohort. Hydrocodone/tramadol/codeine-treated patients exposed to CYP2D6-inhibitor antidepressants (n = 7,043) had a higher crude rate of pain-related ED visits than those taking other antidepressants (n = 5,075) (3.28% vs. 1.87%), with an adjusted odds ratio (aOR) of 1.75 (95% CI: 1.36 to 2.24). Similarly, in the oxycodone cohort, CYP2D6-inhibitor antidepressant-exposed individuals (n = 3,206) had a higher crude rate of ED visits than individuals exposed to other antidepressants (n = 2,341) (5.02% vs. 3.37%), with aOR of 1.70 (95% CI: 1.27-2.27). Similar findings were observed in secondary and sensitivity analyses. Our findings suggest patients with concomitant use of hydrocodone/tramadol/codeine or oxycodone and CYP2D6 inhibitors have more frequent ED visits for pain, which may be due to inadequate pain control.

PMID:38797987 | DOI:10.1002/cpt.3314

J Nurs Scholarsh. 2024 May 26. doi: 10.1111/jnu.12993. Online ahead of print.

ABSTRACT

INTRODUCTION: Genomic healthcare applications have relevance to all healthcare professionals including nursing, and most evidence-based clinical applications impact the quality and safety of healthcare. To guide nursing genomic competency initiatives, the Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics were established through a process of consensus in 2005. A 2009 update incorporated outcome indicators consisting of specific areas of knowledge and clinical performance indicators, to help support academic integration. Almost 20 years have elapsed since these competencies were first established, yet incorporating the competencies into general and specialty scope and standards of nursing practice is inconsistent, competency integration into curricula is highly uneven, continuing education in genomics for nurses is limited, and the genomic capacity of the nursing workforce remains low. These deficits have persisted despite substantial advances in genomic technology which substantially reduced costs and increased evidence-based clinical applications, including direct to consumer genomic tests, the integration of genomics into evidence-based guidelines, and evidence that genomics impacts the quality and safety of healthcare.

DESIGN: The aim of this project was to update and achieve consensus on genomic competencies applicable to all registered nurses. This was a mixed methods study.

METHODS: The update to the competencies was performed based first on a literature review to update the competencies based on the current state of the evidence. Using the updated content, a modified Delphi study was conducted with registered nurse panelists from clinical, academic, and research settings. Once consensus was achieved, the competencies were made available through the American Nurses Association for public comment. Public comments were then reviewed and integrated as needed.

RESULTS: The literature review resulted in a transition from genetics to genomics, given the reduction in costs, which resulted in an expansion of the scope of testing in both the germline and somatic contexts. Two Delphi rounds were required to reach consensus prior to the public comment period. Public comments were solicited through the American Nurses Association, and each comment was reviewed by the authors and addressed as indicated.

CONCLUSION: The Essentials of Genomic Nursing: Competencies and Outcome Indicators constitute the minimum competency in genomics required of all registered nurses regardless of the level of academic training, role, or specialty.

CLINICAL RELEVANCE: Evidence-based genomic applications span the entire healthcare continuum and, therefore, are relevant for all registered nurses regardless of academic training, role, practice setting, or clinical expertise. These competencies serve as the guide for the minimum requirements for registered nurse practice as well as guide curricula and continuing education for all registered nurses, including but not limited to administrators, educators, nursing leaders, practicing nurses, and researchers.

PMID:38797885 | DOI:10.1111/jnu.12993

BMC Psychiatry. 2024 May 27;24(1):394. doi: 10.1186/s12888-024-05764-6.

ABSTRACT

BACKGROUND: Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses.

METHODS: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses.

RESULTS: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects.

CONCLUSIONS: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

PMID:38797832 | DOI:10.1186/s12888-024-05764-6

Dermatol Clin. 2024 Jul;42(3):439-469. doi: 10.1016/j.det.2024.02.005. Epub 2024 Mar 22.

ABSTRACT

This review highlights advances made in psoriasis genetics, including findings from genome-wide association studies, exome-sequencing studies, and copy number variant studies. The impact of genetic variants on various comorbidities and therapeutic responses is discussed.

PMID:38796275 | DOI:10.1016/j.det.2024.02.005

Genes (Basel). 2024 Apr 26;15(5):554. doi: 10.3390/genes15050554.

ABSTRACT

BACKGROUND: MUTYH germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue.

METHODS: we used Sanger sequencing and immunohistochemistry to search for a second MUTYH variant in the tumoral DNA and to assess protein expression, respectively.

RESULTS: we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the MUTYH protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced.

CONCLUSIONS: our results fail to demonstrate that germinal monoallelic MUTYH variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the MUTYH protein in many tumors suggests its dysregulation regardless of MUTYH genetic status.

PMID:38790183 | PMC:PMC11120896 | DOI:10.3390/genes15050554