Elife. 2023 Mar 24;12:e75191. doi: 10.7554/eLife.75191. Online ahead of print.

ABSTRACT

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.

PMID:36961502 | DOI:10.7554/eLife.75191

Medicine (Baltimore). 2023 Mar 24;102(12):e33210. doi: 10.1097/MD.0000000000033210.

ABSTRACT

To investigate the mechanism of action of the classical formula Ling-Gui-Zhu-Gan (LGZG) decoction in treating type 2 diabetes mellitus based on network pharmacology and molecular docking. The active ingredients and targets of LGZG decoction were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database and mapped using Cytoscape software to show their interrelationships. GeneCards, Pharmacogenomics Knowledge Base, OMIM, Therapeutic Target Database, and Drugbank databases were used to obtain targets related to type 2 diabetes; protein-protein interaction networks were established with the help of the STRING platform. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on selected core targets with the help of the Metascape platform. Finally, the AutoDock platform was used to perform molecular docking and display the results by Pymol software. One hundred twenty-one active ingredients, 216 effective target genes, 11,277 type 2 diabetes mellitus-related genes, 210 crossover genes, and 18 core genes were obtained for LGZG decoction. The results obtained by Kyoto Encyclopedia of Genes and Genomes indicated that the advanced glycosylation end products-receptor of advanced glycosylation end products signaling pathway, the phosphatidylinositol 3 kinase-Akt signaling pathway, and HIF-1 signaling pathway might be the key signaling pathways. Molecular docking showed that the binding energy of quercetin, kaempferol, naringenin, and licorice chalcone A to the core target genes were all <5.0 kJ-mol-1, with good affinity. In this study, the potential active ingredients and mechanisms of action of LGZG decoction in the treatment of type 2 diabetes were initially investigated, which provided a basis for the in-depth study of its drug basis and mechanisms of action.

PMID:36961137 | DOI:10.1097/MD.0000000000033210

Br J Clin Pharmacol. 2023 Mar 24. doi: 10.1111/bcp.15721. Online ahead of print.

ABSTRACT

AIM: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes. Methods\ The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio.

RESULTS: A total of 229 patients were included. Highly significant, positive correlations (P <0.0001) were observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ >0.6). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P <0.0001).

CONCLUSIONS: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.

PMID:36960588 | DOI:10.1111/bcp.15721

Indian J Pharmacol. 2023 Jan-Feb;55(1):27-33. doi: 10.4103/ijp.ijp_706_22.

ABSTRACT

OBJECTIVE: Human cytochrome p450 enzymes play an important role in the metabolism of various substances. The CYP2C subfamily consists of various important drug-metabolizing enzymes such as CYP2C9 and CYP2C19. The objectives of the study include the determination of the frequency of genetic variants (CYP2C9*2, CYP2C9*3, and CYP2C19*2) of selected enzymes using allele-specific polymerase chain reaction (ASPCR) and its comparison with Indian as well as global past frequencies. We also aimed to study the impact of genetic mutation on clopidogrel efficacy and compare the efficacies between patients with and without CYP2C19*2 genetic variant.

METHODOLOGY: In this study, the prevalence of variants CYP2C19*2, CYP2C9*2, and CYP2C9*3, the most popular variants of the respective enzymes, was determined using the ASPCR method. The correlation between the CYP2C19*2 variant and the antiplatelet activity of clopidogrel was studied using platelet aggregation assay (PAA).

RESULTS: The determined frequencies of CYP2C19*2, CYP2C9*2, and CYP2C9*3 are 46%, 9%, and 12%. These frequencies are indicative of homozygous as well as heterozygous mutations. Reduced clopidogrel efficacy was observed in patients with a heterozygous mutation of CYP2C19*2 variant.

CONCLUSIONS: The observed frequencies are not significantly different from that observed in earlier reported studies conducted across India and the world. Antiplatelet activity, as measured using the PAA method, was significantly lesser in patients having the CYP2C19*2 variant. The therapy failure in these patients can lead to serious cardiovascular consequences, and we propose determining the presence of the CYP2C19*2 variant before initiation of clopidogrel therapy.

PMID:36960518 | DOI:10.4103/ijp.ijp_706_22

Hum Genomics. 2023 Mar 23;17(1):27. doi: 10.1186/s40246-023-00474-8.

ABSTRACT

BACKGROUND: Pharmacists' contribution to pharmacogenomics (PGx) implementation in clinical practice is vital, but a great proportion of them are not aware of PGx and its applications. This highlights the university education's crucial role to prepare pharmacists to face future challenges in such a constantly evolving and demanding environment.

OBJECTIVES: Our study aims to examine pharmacy students' training satisfaction, knowledge, self-confidence and attitudes towards PGx on their intentions for postgraduate training in PGx and personalised medicine (PM).

METHODS: An initial model on students' intention to pursue postgraduate training in PGx and PM and its predicting factors, based on the Theory of Planned Behaviour (TPB), was proposed. Based on it, a questionnaire was developed and distributed to 346 pharmacy students of all study years, capturing the selected factors influencing students' intentions to postgraduate training in PGx and PM, as well as their demographics. Structural equation modelling (SEM) analysis was employed to determine the effects of both the examined factors and demographics on students' intentions.

RESULTS: Students did not consider themselves adequately prepared for using PGx in clinical practice. Their attitudes towards PGx implementation were the most important factor influencing their intentions to pursue postgraduate training in PGx and PM. Other factors such as self-confidence and training satisfaction also affected students' intentions, but to a lower extent. Students of the last two study years (40% of the whole sample) and male (36%) students stated to be less willing to pursue PGx-related studies in the future. Only 10% of the participants claimed to have undergone a recent PGx or genetic test, but this did not affect their intentions.

CONCLUSION: There is an important gap in pharmacy school curriculum regarding PGx and PM training which coupled with the slow rate of PGx and PM implementation into clinical practice seems to restrain students' aspiration to further expand their knowledge and horizons in terms of PGx and PM.

PMID:36959668 | DOI:10.1186/s40246-023-00474-8

Curr Pharm Teach Learn. 2023 Mar 21:S1877-1297(23)00028-X. doi: 10.1016/j.cptl.2023.02.028. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Many medications contain labeling information related to pharmacogenomics. Effective education in this area is critical to ensure that future healthcare professionals are equipped with the skills needed to optimize patient therapy based on genetic testing results. This study focused on a novel elective course designed to educate students in pharmacogenomics.

EDUCATIONAL ACTIVITY AND SETTING: We developed a one credit hour pharmacogenomics elective course divided into three main content areas. The first section incorporated traditional lecture to review and cover new content not otherwise covered in the curriculum. The second section applied foundational content from the first session through an educational review game and simulated business plan. The third section of the course provided students an overview of laboratory techniques and sample collection procedures. To evaluate the effectiveness of these activities, students provided feedback through course evaluations and completed pre- and posttests on basic pharmacogenomics content.

FINDINGS: Overall, the course improved knowledge among students, and students provided positive feedback. Students averaged 9% higher on the posttest compared to the pretest (P = .03). Course evaluations trended positive with ratings close to "strongly agree." The most frequent comments stated an appreciation for the interactive components of the course and recommended increasing the elective to two credit hours.

SUMMARY: Through incorporation of novel lab techniques, game-based learning, and an innovative business plan process, the course increased student knowledge and received positive feedback. These new techniques could serve as a model for other pharmacogenomics training programs.

PMID:36959050 | DOI:10.1016/j.cptl.2023.02.028

JCO Precis Oncol. 2023 Mar;7:e2200580. doi: 10.1200/PO.22.00580.

ABSTRACT

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most prevalent cause of childhood cancer and requires a long course of therapy consisting of three primary phases with interval intensification blocks. Although these phases are necessary to achieve remission, the primary chemotherapeutic agents have potentially serious toxicities, which may lead to delays or discontinuations of therapy. The purpose of this study was to perform a comprehensive pharmacogenomic evaluation of common antileukemic agents and develop a polygenic toxicity risk score predictive of the most common toxicities observed during ALL treatment.

METHODS: This cross-sectional study included 75 patients with pediatric ALL treated between 2012 and 2020 at the University of Florida. Toxicity data were collected within 100 days of initiation of therapy using CTCAE v4.0 for toxicity grading. For pharmacogenomic evaluation, single-nucleotide polymorphisms (SNPs) and genes were selected from previous reports or PharmGKB database. 116 unique SNPs were evaluated for incidence of various toxicities. A multivariable multi-SNP modeling for up to 3-SNP combination was performed to develop a polygenic toxicity risk score of prognostic value.

RESULTS: We identified several SNPs predictive of toxicity phenotypes in univariate analysis. Further multivariable SNP-SNP combination analysis suggest that susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. For 3-SNPscore models, patients with high scores experienced increased risk of GI (P = 2.07E-05, 3 SNPs: TYMS-rs151264360/FPGS-rs1544105/GSTM1-GSTM5-rs3754446), neurologic (P = .0005, 3 SNPs: DCTD-rs6829021/SLC28A3-rs17343066/CTPS1-rs12067645), endocrine (P = 4.77E-08, 3 SNPs: AKR1C3-rs1937840/TYMS-rs2853539/CTH-rs648743), and heme toxicities (P = .053, 3 SNPs: CYP3A5-rs776746/ABCB1-rs4148737/CTPS1-rs12067645).

CONCLUSION: Our results imply that instead of a single-SNP approach, SNP-SNP combinations in multiple genes in drug pathways increases the robustness of prediction of toxicity. These results further provide promising SNP models that can help establish clinically relevant biomarkers allowing for greater individualization of cancer therapy to maximize efficacy and minimize toxicity for each patient.

PMID:36952646 | DOI:10.1200/PO.22.00580

Front Pharmacol. 2023 Mar 6;14:1083134. doi: 10.3389/fphar.2023.1083134. eCollection 2023.

ABSTRACT

Background: The genetic factors in assessing therapeutic efficacy and predicting antihypertensive drug response are unclear. Therefore, this study aims to identify the associations between variants and antihypertensive drug response. Methods: A longitudinal study including 1837 hypertensive patients was conducted in Northern China and followed up for a median 2.24 years. The associations of 11 candidate variants with blood pressure changes in response to antihypertensive drugs and with the risk of cardiovascular events during the follow-up were examined. The dual-luciferase assay was carried out to assess the effect of genetic variants on gene transcriptional activity. Results: The variant rs11039149A>G in the promoter of nuclear receptor subfamily 1 group H member 3 (NR1H3) was associated with the change in systolic blood pressure (ΔSBP) in response to calcium channel blockers (CCBs) monotherapy. Patients carrying rs11039149AG genotype showed a significant increase of systolic blood pressure (SBP) at follow-up compared with AA carriers, and the difference of ΔSBP between AG and AA carriers was 5.94 mm Hg (95%CI: 2.09-9.78, p = 0.002). In 1,184 patients with CCBs therapy, SBP levels decreased in AA carriers, but increased in AG carriers, the difference of ΔSBP between AG and AA carriers was 8.04 mm Hg (95%CI: 3.28-12.81, p = 0.001). Further analysis in 359 patients with CCBs monotherapy, the difference of ΔSBP between AG and AA carriers was 15.25 mm Hg (95%CI: 6.48-24.02, p = 0.001). However, there was no significant difference in ΔSBP between AG and AA carriers with CCBs multitherapy. The rs11039149A>G was not associated with the cardiovascular events incidence during the follow-up. Additionally, transcriptional factor forkhead box C1 (FOXC1) bound to the NR1H3 promoter containing rs11039149A and significantly increased the transcriptional activity, while rs11039149 A to G change led to a loss-of-function and disabled FOXC1 binding. For the other 10 variants, associations with blood pressure changes or risk of cardiovascular events were not observed. Conclusion: Hypertensive patients with rs11039149AG genotype in the NR1H3 gene have a significant worse SBP control in response to CCBs monotherapy compared with AA carriers. Our findings suggest that the NR1H3 gene might act as a promising genetic factor to affect individual sensitivity to antihypertensive drugs.

PMID:36950018 | PMC:PMC10025344 | DOI:10.3389/fphar.2023.1083134

Obes Surg. 2023 Mar 22. doi: 10.1007/s11695-023-06526-1. Online ahead of print.

ABSTRACT

PURPOSE: Roux-en-Y gastric bypass (RYGB) involves alterations of the gastrointestinal tract resulting in altered absorption. Patients with obesity have a higher prevalence of depression, and antidepressants are often prescribed. Alterations caused by RYGB could modify drug bioavailability and cause potential subtherapeutic plasma concentrations, increasing the risk of depressive relapse. The aim of this study was to describe the evolution of trough drug dose-normalized antidepressant plasma concentrations before and after RYGB.

MATERIALS AND METHODS: This naturalistic prospective case series considers patients with trough plasma concentrations in a 1-year timeframe before and after RYGB. Only antidepressants prescribed to at least three patients were included in the present study.

RESULTS: Thirteen patients (n = 12 females, median age 44 years, median BMI before intervention = 41.3 kg/m2) were included. Two patients were treated concurrently with fluoxetine and trazodone; the remaining patients were all treated with antidepressant monotherapy. Therapeutic drug monitoring (TDM) values for duloxetine (n = 3), escitalopram (n = 4), fluoxetine (n = 4), and trazodone (n = 4) before (median 4.7 weeks) and after (median 21.3 weeks) RYGB intervention were analyzed. Compared to preintervention, median [interquartile range] decreases in dose-normalized trough plasma concentrations for duloxetine (33% [- 47; - 23]), escitalopram (43% [- 51; - 31]), fluoxetine (9% [- 20; 0.2]), and trazodone (16% [- 29; 0.3]) were observed.

CONCLUSION: This study shows a decrease in plasma antidepressant concentrations following RYGB. TDM before and after RYGB, in addition to close monitoring of psychiatric symptomatology, may help optimize antidepressant treatment after bariatric surgery. These results also highlight the need for prospective studies assessing the clinical evidence available through TDM in these patients.

PMID:36949223 | DOI:10.1007/s11695-023-06526-1

Pharmacogenomics. 2023 Mar 22. doi: 10.2217/pgs-2023-0020. Online ahead of print.

NO ABSTRACT

PMID:36946361 | DOI:10.2217/pgs-2023-0020

Pharmacogenomics. 2023 Mar 22. doi: 10.2217/pgs-2022-0187. Online ahead of print.

ABSTRACT

Background: The presence of polymorphisms in the TPMT gene is associated with adverse effects in patients treated with standard doses of thiopurine drugs. Scientific evidence recognizes significant ethnic differences in their frequencies and how their early identification can prevent clinical complications. Methods: 150 healthy residents of Aragua, Venezuela were enrolled. The SNPs c.460G>A and c.719A>G were detected by PCR-restriction fragment length polymorphism assay and c.238G>C by allele-specific PCR. Results: All genotype polymorphisms were heterozygous. TPMT*1/*3A, TPMT*1/*3C and TPMT*1/*2 genotypes were found in 4.0, 2.0 and 0.7%, respectively. Conclusion: 6.7% of individuals have an intermediate TPMT activity. These findings support the importance of prior genotyping of TPMT in Venezuelan patients who require thiopurine drug therapy.

PMID:36946340 | DOI:10.2217/pgs-2022-0187

Pharmacogenomics. 2023 Mar 22. doi: 10.2217/pgs-2022-0164. Online ahead of print.

ABSTRACT

Aim: We previously conducted exome-wide association study in acute lymphoblastic leukemia patients and identified association of five SNPs with asparaginase-related thrombosis. Here we aimed to replicate these findings in an independent patient cohort and through analyses in vitro. Patients & methods: SNPs located in IL16, MYBBP1A, PKD2L1, RIN3 and MPEG1 genes were analyzed in patients receiving Dana-Farber Cancer Institute acute lymphoblastic leukemia treatment protocols 05-001 and 11-001. Thrombophilia-related variations were also analysed. Results: IL16 rs11556218 conferred higher risk of thrombosis and higher in vitro sensitivity to asparaginase. The association was modulated by the treatment protocol, risk group and immunophenotype. A crosstalk between factor V Leiden, non-O blood groups and higher risk of thrombosis was also seen. Conclusion: IL16 and factor V Leiden variations are implicated in asparaginase-related thrombosis.

PMID:36946317 | DOI:10.2217/pgs-2022-0164

Pharmacogenomics. 2023 Mar 22. doi: 10.2217/pgs-2022-0149. Online ahead of print.

ABSTRACT

Background: Variability in the pharmacokinetics and pharmacodynamics of oxycodone in children undergoing surgery could be due to genetic polymorphisms. Materials & methods: The authors studied the association between clinical outcomes and pharmacogenes in children undergoing major surgery. A total of 89 children (35 undergoing pectus excavatum repair and 54 undergoing spinal fusion) were recruited. Results: OPRM1 SNP rs6902403 showed an association with maximum pain score and total morphine equivalent dose (p < 0.05). Other polymorphisms in OPRM1 SNP, PXR, COMT and ABCB1 were also shown to be associated with average morphine equivalent dose, length of hospital stay and maximum surgical pain (p < 0.05). Conclusion: This study demonstrates novel associations between the above pharmacogenes and oxycodone's pharmacokinetics as well as postoperative outcomes in children. Clinical trial registration: NCT03495388 (ClinicalTrials.gov).

PMID:36946298 | DOI:10.2217/pgs-2022-0149

medRxiv. 2023 Mar 9:2023.03.07.23286875. doi: 10.1101/2023.03.07.23286875. Preprint.

ABSTRACT

BACKGROUND: SGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes - including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.

METHODS: Canagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including drug-induced increases in urinary excretion of glucose, sodium, and uric acid.

RESULTS: This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6×10 -5 ), serum creatinine (+0.05 mg/dL; p=8×10 -4 ), and serum uric acid (-0.90 mg/dL; p=5×10 -10 ). The effects of sex on glucosuria depended upon how data were normalized. Whereas males' responses were ∼60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m 2 .

CONCLUSIONS: Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study ( NCT02891954 ) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function.

REGISTRATION: NCT02462421 ( clinicaltrials.gov ).

FUNDING: Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.

PMID:36945579 | PMC:PMC10029014 | DOI:10.1101/2023.03.07.23286875

Genes Cells. 2023 Mar 21. doi: 10.1111/gtc.13026. Online ahead of print.

ABSTRACT

The extracellular-signal-regulated-kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as pancreatic cancers. ACAGT-007a (GT-7), an anti-cancer compound, stimulates ERK phosphorylation, thereby inducing growth inhibition and apoptosis in T3M4 pancreatic cancer cells. However, how GT-7 stimulates ERK phosphorylation and induces apoptosis in ERK-active T3M4 cells remains unclear. To look into the mechanism, we performed a spatiotemporal analysis of ERK phosphorylation mediated by GT-7 in T3M4 cells. The immunoblotting showed that GT-7 stimulates ERK phosphorylation within 1 hr, which was more remarkable after 2 hr. Importantly, apoptosis induction as evaluated by the cleaved Caspase-3 was observed only after 2 hr incubation with GT-7. The immunofluorescence staining revealed the enrichment of phosphorylated ERK (phospho-ERK) in the nucleus upon 1 hr incubation with GT-7. Fractionation experiments showed that GT-7 increases phospho-ERK levels in the cytoplasm within 1 hr, whereas nuclear phospho-ERK accumulation is observed after 2 hr incubation with GT-7. MEK inhibition by U0126 significantly diminishes nuclear phospho-ERK distribution and apoptosis induction stimulated by GT-7. Thus, GT-7 may initiate the induction of ERK phosphorylation in the cytoplasm, which leads to phospho-ERK enrichment in the nucleus. This nuclear phospho-ERK accumulation by GT-7 precedes and may underlie apoptosis induction in T3M4.

PMID:36945130 | DOI:10.1111/gtc.13026

Ann Fam Med. 2023 Jan 1;(21 Suppl 1). doi: 10.1370/afm.21.s1.3642.

ABSTRACT

Context: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for many medications commonly prescribed prior to hospital discharge, yet there is limited data regarding the contribution of gene-x-drug interactions to hospital readmissions. Objective: The present study evaluated the relationship between prescription of CPIC medications prescribed within 30 days of hospital admission and 90-day hospital readmission from 2010-2020. Study Design and Analysis: Retrospective cohort study. Multivariable logistic regression analyzed the association between one or more gene-x-drug interactions with 90-day readmission. Population Studied: Primary care patients (N=10,104) who underwent sequencing with a 14-gene pharmacogenetic panel. Intervention/Instrument: Primary care physicians ordered a Color genetic panel that included pharmacogenetic genes reported through electronic health records. Outcome Measures: The primary endpoint was 90-day hospital readmission. The presence of at least one pharmacogenetic indicator for a medication prescribed within 30 days of hospital admission was considered a gene-x-drug interaction. Results: There were 2,211/2,354 (93.9%) admitted patients who were prescribed at least one CPIC medication. Univariate analyses indicated that the presence of at least one identified gene-x-drug interaction increased risk of 90-day readmission by more than 40% (OR=1.42, 95% confidence interval (CI) 1.09-1.84)(p=0.01). A multivariable model adjusting for age, race, sex, employment status, body mass index, and medical conditions, slightly attenuated the effect (OR=1.32, 95% CI 1.02-1.73)(p=0.04). Conclusions: Our results suggest that the presence of one or more CPIC gene-x-drug interactions increases the risk of 90-day hospital readmission, even after adjustment for demographic and clinical risk factors.

PMID:36944076 | DOI:10.1370/afm.21.s1.3642

Microbiol Spectr. 2023 Mar 21:e0487022. doi: 10.1128/spectrum.04870-22. Online ahead of print.

ABSTRACT

In order to ensure the prevention and control of methicillin-resistant Staphylococcus aureus (MRSA) infection, rapid and accurate detection of pathogens and their resistance phenotypes is a must. Therefore, this study aimed to develop a fast and precise nucleic acid detection platform for identifying S. aureus and MRSA. We initially constructed a CRISPR-Cas12a detection system by designing single guide RNAs (sgRNAs) specifically targeting the thermonuclease (nuc) and mecA genes. To increase the sensitivity of the CRISPR-Cas12a system, we incorporated PCR, loop-mediated isothermal amplification (LAMP), and recombinase polymerase amplification (RPA). Subsequently, we compared the sensitivity and specificity of the three amplification methods paired with the CRISPR-Cas12a system. Finally, the clinical performance of the methods was tested by analyzing the fluorescence readout of 111 clinical isolates. In order to visualize the results, lateral-flow test strip technology, which enables point-of-care testing, was also utilized. After comparing the sensitivity and specificity of three different methods, we determined that the nuc-LAMP-Cas12a and mecA-LAMP-Cas12a methods were the optimal detection methods. The nuc-LAMP-Cas12a platform showed a limit of detection (LOD) of 10 aM (~6 copies μL-1), while the mecA-LAMP-Cas12a platform demonstrated a LOD of 1 aM (~1 copy μL-1). The LOD of both platforms reached 4 × 103 fg/μL of genomic DNA. Critical evaluation of their efficiencies on 111 clinical bacterial isolates showed that they were 100% specific and 100% sensitive with both the fluorescence readout and the lateral-flow readout. Total detection time for the present assay was approximately 80 min (based on fluorescence readout) or 85 min (based on strip readout). These results indicated that the nuc-LAMP-Cas12a and mecA-LAMP-Cas12a platforms are promising tools for the rapid and accurate identification of S. aureus and MRSA. IMPORTANCE The spread of methicillin-resistant Staphylococcus aureus (MRSA) poses a major threat to global health. Isothermal amplification combined with the trans-cleavage activity of Cas12a has been exploited to generate diagnostic platforms for pathogen detection. Here, we describe the design and clinical evaluation of two highly sensitive and specific platforms, nuc-LAMP-Cas12a and mecA-LAMP-Cas12a, for the detection of S. aureus and MRSA in 111 clinical bacterial isolates. With a limit of detection (LOD) of 4 × 103 fg/μL of genomic DNA and a turnaround time of 80 to 85 min, the present assay was 100% specific and 100% sensitive using either fluorescence or the lateral-flow readout. The present assay promises clinical application for rapid and accurate identification of S. aureus and MRSA in limited-resource settings or at the point of care. Beyond S. aureus and MRSA, similar CRISPR diagnostic platforms will find widespread use in the detection of various infectious diseases, malignancies, pharmacogenetics, food contamination, and gene mutations.

PMID:36943040 | DOI:10.1128/spectrum.04870-22

Radiol Oncol. 2023 Mar 22;57(1):111-120. doi: 10.2478/raon-2023-0003. eCollection 2023 Mar 1.

ABSTRACT

BACKGROUND: Tramadol is an opioid analgesic often used for pain management after breast cancer surgery. Its analgesic activity is due to the activation of the μ-opioid receptor, encoded by the OPRM1 gene. This study investigated the association of genetic variability in OPRM1 and its regulatory miRNA genes with outcomes of tramadol/paracetamol treatment after breast cancer surgery with axillary lymphadenectomy.

PATIENTS AND METHODS: The study included 113 breast cancer patients after breast cancer surgery with axillary lymphadenectomy treated with either 75/650 mg or 37.5/325 mg of tramadol with paracetamol for pain relief within the randomized clinical trial KCT 04/2015-DORETAonko/si at the Institute of Oncology Ljubljana. All patients were genotyped for OPRM1 rs1799971 and rs677830, MIR23B rs1011784, and MIR107 rs2296616 using competitive allele-specific PCR. The association of genetic factors with acute and chronic pain as well as adverse effects of tramadol treatment was evaluated using logistic regression, Fisher's exact test, and Mann-Whitney test.

RESULTS: The investigated OPRM1 related polymorphisms were not associated with acute pain assessed with the VAS scale within four weeks after surgery (all P > 0.05). Carriers of at least one polymorphic OPRM1 rs1799971 allele had a higher risk of constipation in the first four weeks after surgery compared to non-carriers (OR = 4.5, 95% CI = 1.6-12.64, P = 0.004). Carriers of at least one polymorphic OPRM1 rs677830 allele had a higher risk of constipation after third week of tramadol treatment (OR = 3.11, 95% CI = 1.08-8.89, P = 0.035). Furthermore, carriers of two polymorphic MIR23B rs1011784 alleles had a higher risk of nausea after 28 days of tramadol treatment (OR = 7.35, 95% CI = 1.27-42.6, P = 0.026), while heterozygotes for MIR107 rs2296616 allele had a lower risk of nausea after 21 days of tramadol treatment (OR = 0.21, 95% CI = 0.05-0.87, P = 0.031). In carriers of two polymorphic MIR107 rs2296616 alleles, chronic pain was significantly more common than in carriers of two wild-type alleles (P = 0.004). Carriers of at least one polymorphic MIR23B rs1011784 allele experienced more neuropathic pain after adjustment for tramadol dose (OR = 2.85, 95% CI = 1.07-7.59, P = 0.036), while carriers of at least one polymorphic OPRM1 rs677830 allele experienced less neuropathic pain compared to carriers of two wild-type alleles (OR = 0.38, 95% CI = 0.15-0.99, P = 0.047).

CONCLUSIONS: Genetic variability of OPRM1 and genes coding for miRNAs that could affect OPRM1 expression may be associated with adverse effects of tramadol/paracetamol treatment as well as with chronic and neuropathic pain after breast cancer surgery with axillary lymphadenectomy.

PMID:36942908 | DOI:10.2478/raon-2023-0003

J Pharm Pharm Sci. 2023 Jan 30;26:11136. doi: 10.3389/jpps.2023.11136. eCollection 2023.

ABSTRACT

Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.

PMID:36942299 | PMC:PMC9990631 | DOI:10.3389/jpps.2023.11136

Ann Rheum Dis. 2023 Mar 20:ard-2022-223618. doi: 10.1136/ard-2022-223618. Online ahead of print.

ABSTRACT

OBJECTIVES: Teriparatide (TPTD) is an effective treatment for osteoporosis but the individual response to therapy is variable for reasons that are unclear. This study aimed to determine whether the response to TPTD might be influenced by genetic factors.

METHODS: We searched for predictors of the response of bone mineral density (BMD) to TPTD using a two-stage genome-wide association study in 437 patients with osteoporosis from three referral centres. Demographic and clinical data including the response of BMD to treatment at the lumbar spine and hip were extracted from the medical records of each participant.

RESULTS: Allelic variation at rs6430612 on chromosome 2, close to the CXCR4 gene was associated with the response of spine BMD to TPTD at a genome wide significant level (p=9.2×10-9 beta=-0.35 (-0.47 to -0.23)). The increase in BMD was almost twice as great in AA homozygotes at rs6430612 as compared with GG homozygotes with intermediate values in heterozygotes. The same variant was also associated with response of femoral neck and total hip BMD (p=0.007). An additional locus on chromosome 19 tagged by rs73056959 was associated with the response of femoral neck BMD to TPTD (p=3.5×10-9, beta=-1.61 (-2.14 to -1.07)).

CONCLUSIONS: Genetic factors influence the response to TPTD at the lumbar spine and hip with a magnitude of effect that is clinically relevant. Further studies are required to identify the causal genetic variants and underlying mechanisms as well as to explore how genetic testing for these variants might be implemented in clinical practice.

PMID:36941031 | DOI:10.1136/ard-2022-223618