Pharmacogenomics. 2022 Sep 28:0. doi: 10.2217/pgs-2022-0075. Online ahead of print.

ABSTRACT

Objective: To develop an accurate and rapid real-time PCR technique for HLA-B*15:02 genotyping and investigate HLA-B*15:02 allele frequency in four ethnic populations in China. Materials & methods: Based on the highly specific representative markers, a real-time PCR assay was developed for HLA-B*15:02 genotyping, and HLA-B*15:02 allele frequencies were screened in four ethnic populations of China. Sequence-based typing was used to validate the accuracy of the assay. Results: The sensitivity and specificity of the assay were 100%, and the detection limit was 0.2 ng. The frequency of HLA-B*15:02 alleles distributed in the Bouyei population was significantly higher than in the Han group (p < 0.01). Neither the Tibetan nor the Uyghur population carried the HLA-B*15:02 haplotype. Conclusion: The authors developed an accurate HLA-B*15:02 genotyping method for evaluating the risk of adverse drug reactions induced by carbamazepine in various ethnic populations in China.

PMID:36169168 | DOI:10.2217/pgs-2022-0075

WIREs Mech Dis. 2022 Sep 27:e1585. doi: 10.1002/wsbm.1585. Online ahead of print.

ABSTRACT

Cancer treatment is gradually evolving from the classical use of nonspecific cytotoxic drugs targeting generic mechanisms of cell growth and proliferation. Instead, new "patient-specific treatment paradigms" that are based on an individual patient's tumor-specific molecular features are emerging, and these include "druggable" genomic alterations such as oncogenic driver mutations, downstream activities of cancer-signaling pathways, and the expression of specific genes involved in tumorigenesis and cancer progression. This evolving landscape of making evidence-based treatment decisions forms the foundation of precision oncology, which aims to deliver "the right drug, to the right patient and at the right time". The long-term vision for this approach is to maximize the treatment efficacy while minimizing exposure to ineffective therapy and reducing co-morbidity-related side effects. Successful clinical translation and implementation of this vision have the potential to revolutionize treatment paradigms from predominantly reactive, to more evidence-based, proactive and predictive care. In this article, we review the past and current approaches in precision oncology, and describe their remarkable power and limitations. We also speculate on the evolution of newly emerging methodologies of the future that can be used to address some of the key challenges associated with the existing paradigms. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Cancer > Molecular and Cellular Physiology Cancer > Computational Models.

PMID:36168283 | DOI:10.1002/wsbm.1585

Pediatr Res. 2022 Sep 27. doi: 10.1038/s41390-022-02313-3. Online ahead of print.

ABSTRACT

BACKGROUND: Children with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear.

METHODS: Prescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC.

RESULTS: Overall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors.

CONCLUSION: GS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC.

IMPACT: Polypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity.

PMID:36167815 | DOI:10.1038/s41390-022-02313-3

Chem Commun (Camb). 2022 Sep 27. doi: 10.1039/d2cc04254a. Online ahead of print.

ABSTRACT

Microscale covalent organic polymers with a unique 3D hollow wool ball-like morphology have been woven from 1D nanorods by a cascade emulsion strategy with a large surface area (284 m2 g-1), which showed great potential for simultaneous removal (Qmax, 358.15 mg g-1) and fluorescent detection (detection limit, 8.0 μg L-1) of bisphenol A.

PMID:36165975 | DOI:10.1039/d2cc04254a

Elife. 2022 Sep 27;11:e75521. doi: 10.7554/eLife.75521.

ABSTRACT

Duchenne muscular dystrophy (DMD) affects myofibers and muscle stem cells, causing progressive muscle degeneration and repair defects. It was unknown whether dystrophic myoblasts-the effector cells of muscle growth and regeneration-are affected. Using transcriptomic, genome-scale metabolic modelling and functional analyses, we demonstrate, for the first time, convergent abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx myoblasts lacking full-length dystrophin, the expression of 170 genes was significantly altered. Myod1 and key genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signalling and fibrosis genes) were significantly downregulated. Gene ontology analysis indicated enrichment in genes involved in muscle development and function. Functionally, we found increased myoblast proliferation, reduced chemotaxis and accelerated differentiation, which are all essential for myoregeneration. The defects were caused by the loss of expression of full-length dystrophin, as similar and not exacerbated alterations were observed in dystrophin-null Dmdmdx-βgeo myoblasts. Corresponding abnormalities were identified in human DMD primary myoblasts and a dystrophic mouse muscle cell line, confirming the cross-species and cell-autonomous nature of these defects. The genome-scale metabolic analysis in human DMD myoblasts showed alterations in the rate of glycolysis/gluconeogenesis, leukotriene metabolism, and mitochondrial beta-oxidation of various fatty acids. These results reveal the disease continuum: DMD defects in satellite cells, the myoblast dysfunction affecting muscle regeneration, which is insufficient to counteract muscle loss due to myofiber instability. Contrary to the established belief, our data demonstrate that DMD abnormalities occur in myoblasts, making these cells a novel therapeutic target for the treatment of this lethal disease.

PMID:36164827 | DOI:10.7554/eLife.75521

Saudi Pharm J. 2022 Aug;30(8):1181-1192. doi: 10.1016/j.jsps.2022.06.013. Epub 2022 Jun 22.

ABSTRACT

BACKGROUND: The drugs impacted by genetic variants are known as pharmacogenetic (PGx) drugs. Patients' responses to these drugs may vary according to the variability in patients' genetic makeup. Hence, exploring the pharmacogenes that affect drug treatment is vital to ensure optimal therapy and patients' safety. This study aimed to describe the usage rate of PGx drugs and the frequency of relevant variants in the Saudi population.

METHODOLOGY: Prescription patterns over seven years (2015-2021) for Saudi patients on PGx drugs treated at the Ministry of National Guard-Health Affairs (MNG-HA) were investigated. Only registered drugs in the MNG-HA formulary (n = 78) were included. The patients were subgrouped into four age groups: ≤24, 25-44, 45-64, and ≥65 years. Further subgrouping was made according to gender and drugs' therapeutic categories following anatomical therapeutic chemical (ATC) classification.Furthermore, an online searching was carried out to identify the pharmacogenes reported in the literature among healthy Saudis. The search included 45 genes that may affect drug outcomes based on evidence rated by either CPIC (A-B levels) or PharmGKB (1-2 levels).

RESULTS: The screened patients were 1,483,905. Patients on PGx drugs accounted for 46.7% (n = 693,077 patients). The analgesic group was the most prescribed drug category (47%), which included ibuprofen (20.5%), celecoxib (6.3%), tramadol (5.8%), and others. Cardiovascular agents were the second-most utilized drug class (24.4%). Omeprazole was the second most commonly used medication (11.1%) but ranked third as a class (gastroenterology). Females used PGx drugs more frequently than males (53.5% versus 46.5%) and a higher usage rate by patients aged 45-64 years (31.3%) was noted. The cytochrome P450 genes (CYP2C9, CYP2C19, and CYP2D6) were estimated to impact responses of 54.3% (n = 1,156,113) of the used drugs (27.2% are possibly affected by CYP2C9, 12.8% by CYP2C19, and 14.3% by CYP2D6). Thirty-five pharmacogenes that characterize Saudi population and their variants' allele frequencies were identified from previous reports. This study presents the largest reported number of genes that may affect drug therapies among Saudis.

CONCLUSION: This study confirmed that a high percentage of Saudi patients use PGx drugs and various genotypes of certain pharmacogenes are inherited by the Saudi population.

PMID:36164570 | PMC:PMC9508627 | DOI:10.1016/j.jsps.2022.06.013

3 Biotech. 2022 Nov;12(11):287. doi: 10.1007/s13205-022-03363-4. Epub 2022 Sep 21.

ABSTRACT

The outbreak of COVID-19 caused by the coronavirus (SARS-CoV-2) prompted number of computational and laboratory efforts to discover molecules against the virus entry or replication. Simultaneously, due to the availability of clinical information, drug-repurposing efforts led to the discovery of 2-deoxy-d-glucose (2-DG) for treating COVID-19 infection. 2-DG critically accumulates in the infected cells to prevent energy production and viral replication. As there is no clarity on the impact of genetic variations on the efficacy and adverse effects of 2-DG in treating COVID-19 using in silico approaches, we attempted to extract the genes associated with the 2-DG pathway using the Comparative Toxicogenomics Database. The interaction between selected genes was assessed using ClueGO, to identify the susceptible gene loci for SARS-CoV infections. Further, SNPs that were residing in the distinct genomic regions were retrieved from the Ensembl genome browser and characterized. A total of 80 SNPs were retrieved using diverse bioinformatics resources after assessing their (a) detrimental influence on the protein stability using Swiss-model, (b) miRNA regulation employing miRNASNP3, PolymiRTS, MirSNP databases, (c) binding of transcription factors by SNP2TFBS, SNPInspector, and (d) enhancers regulation using EnhancerDB and HaploReg reported A2M rs201769751, PARP1 rs193238922 destabilizes protein, six polymorphisms of XIAP effecting microRNA binding sites, EGFR rs712829 generates 15 TFBS, BECN1 rs60221525, CASP9 rs4645980, SLC2A2 rs5393 impairs 14 TFBS, STK11 rs3795063 altered 19 regulatory motifs. These data may provide the relationship between genetic variations and drug effects of 2-DG which may further assist in assigning the right individuals to benefit from the treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03363-4.

PMID:36164436 | PMC:PMC9491670 | DOI:10.1007/s13205-022-03363-4

Chem Biol Interact. 2022 Sep 23:110190. doi: 10.1016/j.cbi.2022.110190. Online ahead of print.

ABSTRACT

BACKGROUND: Studies have shown that the CDK5R1 gene could have a part in some types of cancer. This study sought to examine the relationship between CDK5R1 expression and prognosis and medication resistance in 13 commonly occurring cancers.

METHOD: The cancer genome atlas data and clinical data were utilized to assess the role of CDK5R1 in malignancies. The expression data of 13 cancers were also integrated and used for the co-expression network. The relationship between CDK5R1 expression and drug resistance and sensitivity was evaluated using pharmacogenomics data. The colorectal cancer (CRC) and breast cancer (BC) were used to confirm the results through the RT-qPCR method.

RESULTS: With the exception of gastric cancer, all common malignancies showed an increase in CDK5R1 expression. Also, outcomes of sensitivity and specificity showed that CDK5R1 level could be a really good potential biomarker. Additionally, CDK5R1 expression was higher in CRC and BC samples compared to adjacent normal, according to RT-qPCR data. In six types of tumors and combined data, a poor prognosis was associated with increased CDK5R1 expression. The CDK5R1-associated genes were connected to the primary oncogenic pathways in cancer cells, according to the co-expression network. Also, CDK5R1 level was significantly linked to the resistance and sensitivity of several chemotherapy drugs and caused the highest resistance to cyclophosphamide.

CONCLUSION: CDK5R1 expression is upregulated in 12 prevalent cancers and can play an oncogenic role. Also, this gene's expression could be used as a biomarker to predict patient survival and medication resistance.

PMID:36162454 | DOI:10.1016/j.cbi.2022.110190

Biomed Pharmacother. 2022 Sep 23;155:113747. doi: 10.1016/j.biopha.2022.113747. Online ahead of print.

ABSTRACT

Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUC0-∞/DW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC0-∞/DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25-50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50-70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007 <p < 0.05) between ABCG2, ABCB1, NAT2 and UGT1A4 polymorphisms and pharmacokinetic variability were observed; further research should elaborate on the clinical relevance of the described associations.

PMID:36162369 | DOI:10.1016/j.biopha.2022.113747

Food Chem. 2022 Sep 21;403:134346. doi: 10.1016/j.foodchem.2022.134346. Online ahead of print.

ABSTRACT

Simultaneous and high-performance detection of pesticides is still a considerable challenge and urgent need. Herein, a dual-emission carbon dots (CDs)-based nonenzymatic fluorescent sensing platform has been developed, which shows excellent sensitivity and selectivity in simultaneously detecting parathion-methyl (MP) and glyphosate. CDs with emissions at 440 nm (bCDs) and 660 nm (rCDs) were prepared by hydrothermal treatment of mulberry leaves and sodium hydroxide. bCDs response to hydrolyzed MP via inner filter effect, while rCDs sense glyphosate with the aid of Cu2+ by static quenching effect. Excellent linear correlations were found for MP (0.3-65.0 μM) and glyphosate (1.0-110.0 μM) with limits of detection at 0.14 and 0.60 μM. Notably, the presented dual-channel strategy was successfully applied in simultaneously detecting MP and glyphosate in food/herbal samples with acceptable recoveries, good precision, and high selectivity. Moreover, an ORlogicgatewas achieved for estimating food, herbal, or environmental safety.

PMID:36162271 | DOI:10.1016/j.foodchem.2022.134346

Mol Carcinog. 2022 Sep 26. doi: 10.1002/mc.23467. Online ahead of print.

ABSTRACT

Lentivirus-based transduction systems are widely used in biological science and cancer biology, including cancer immunotherapy. However, in in vivo transplanted tumor model, the immunogenicity of these transduced cells was not appropriately addressed. Here, we used empty vector-transduced mouse melanoma (B16) and carcinoma (lewis lung carcinoma) cells transplanted tumor model to study the immune response due to the transduction processes. We showed that the overall in vivo tumor growth rate gets reduced in transduced cells only in immune-competent mice but not in nude mice. This data indicate the involvement of the immune system in the in vivo tumor growth restriction in the transduced group. Further studies showed that specific activation of CD8+ T cells might be responsible for restricted tumor growth. Mechanistically, transduced tumor cells show the higher activity of type I interferon, which might play an essential role in this activation. Overall, our data indicate the modulation of the immune system by lentiviral vector transduced tumor cells, which required further studies to explore the mechanisms and better understand the biological significance. Our data also indicate the importance of considering the immunogenicity of transduced cells when analyzing in vivo results, especially in studies related to immunotherapy.

PMID:36161729 | DOI:10.1002/mc.23467

Front Pharmacol. 2022 Aug 31;13:990461. doi: 10.3389/fphar.2022.990461. eCollection 2022.

ABSTRACT

Background: Previous investigations have illustrated that lysyl oxidase family enzymes (LOXs) are contributing factors for tumor progression and remodeling immunomicroenvironment. However, it is scarce regarding comprehensive analysis of LOXs in the predictions of prognosis, chemotherapy and immunotherapy in glioma, the highly invasive brain tumor. Our present work aimed to explore the prognostic value, chemotherapeutic drug sensitivity and immunotherapy according to distinct LOXs expressions in glioma through bioinformatics analysis and experimental verification. Methods: We collected gene expression data and clinical characteristics from the public databases including Chinese Glioma Genome Atlas (CGGA)-325, CGGA-693, the Cancer Genome Atlas (TCGA), IMvigor210 and Van Allen 2015 cohorts. The correlations between the clinicopathological factors and differential LOXs expressions were analyzed. The ROC curve and Kaplan-Meier analysis were conducted to evaluate the prediction ability of prognosis. Chemotherapeutic drug sensitivity via distinct LOXs expression levels was predicted using the pRRophetic package. Immune score, immune cell infiltration and immune checkpoint expression levels were also analyzed through diverse algorithms in R software. Finally, mRNA and protein expressions of LOXs were validated in glioma cells (T98G and A172) by real-time quantitative PCR and Western blot, respectively. Results: Our results demonstrated that high levels of LOXs expressions were positively associated with glioma grades, older age and MGMT unmethylated status while elevations of LOXs were negatively correlated with IDH mutation or 1p/19q co-deletion. Furthermore, the glioma patients with low levels of LOXs also exhibited better prognosis. Also, differential LOXs expressions were associated with at least 12 chemotherapeutic drug sensitivity. Besides, it was also found that glioma patients with high LOXs expressions showed higher enrichment scores for immune cell infiltration and increased levels of immune checkpoints, suggesting the critical role of distinct LOXs expression levels for glioma immunotherapy. The predictive roles of LOXs expression in tumor immunotherapy were also validated in two immunotherapy cohorts including IMvigor 210 and Van Allen 2015. Experimental results revealed that expressions of LOX, LOXL1, LOXL2, and LOXL3 were higher in glioma cell lines at mRNA and protein levels. Conclusion: Our findings altogether indicate that LOXs have potent predictive value for prognosis, chemotherapy and immunotherapy in glioma patients.

PMID:36160460 | PMC:PMC9490755 | DOI:10.3389/fphar.2022.990461

Front Nutr. 2022 Sep 8;9:952056. doi: 10.3389/fnut.2022.952056. eCollection 2022.

ABSTRACT

Vitamin C (Vit C) and iron metabolism are closely related to metabolic disorders. However, the relation between iron storage protein ferritin and Vit C has not been elucidated. We aimed to investigate the crosstalk between Vit C and ferritin and its implications on non-alcoholic fatty liver disease (NAFLD). Clinical information of 3,614 subjects was obtained from the NHANES Public Data 2017-2018. FibroScan data, which estimates liver steatosis and fibrosis and Vit C, were selected to assess factors influencing NAFLD in this cross-sectional study. Ferritin and Vit C among different categories of liver steatosis and fibrosis were assessed by CAP and E value. Logistic regression and RCS models were used to analyze the correlations. In vitro study in hepG2 were conducted to validate the regulations. Ferritin increased while Vit C decreased with more severe hepatic steatosis and hepatic fibrosis (all P < 0.001). Logistic regression models indicated that increased serum ferritin was a risk factor for NAFLD while increased Vit C was a protective factor for NAFLD and hepatic fibrosis after adjusting the continuous and categorical variables. Vitamin C was negatively associated with ferritin. Further mediation analysis identified that ferritin mediates the impact of Vit C on NAFLD (P < 0.05) and cirrhosis (P < 0.001). The experiments on cellular level suggested Vit C alleviated PA/OA induced steatosis and maintains iron homeostasis through inhibiting PA/OA induced upregulation of iron bound protein ferritin and labile iron pool (LIP) induction in hepG2 cells. In conclusion, Vit C was a protective factor, whereas ferritin was a risk factor for hepatic steatosis and fibrosis. Vitamin C alleviated NAFLD and maintained iron homeostasis via ferritin suppression and LIP induction.

PMID:36159474 | PMC:PMC9494736 | DOI:10.3389/fnut.2022.952056

Respirology. 2022 Sep 26. doi: 10.1111/resp.14380. Online ahead of print.

NO ABSTRACT

PMID:36156336 | DOI:10.1111/resp.14380

Schizophr Bull. 2022 Sep 26:sbac133. doi: 10.1093/schbul/sbac133. Online ahead of print.

ABSTRACT

BACKGROUND: Several psychotropic drugs can induce weight gain and metabolic alterations. The authors compared metabolic evolutions of patients switching versus continuing psychotropic treatments with different risk profiles.

METHODS: Patients either switched from a high- to a medium- (N = 36) or low-risk drug (N = 27), from a medium- to a low-risk drug (N = 71), or to a same-risk drug (N = 61). Controls were kept using either a high- (N = 35), medium- (N = 155), or low-risk drug (N = 47). The evolution over 2 years of weight and metabolic parameters was analyzed using linear mixed-effect models, also examining the influence of polygenic risk scores for body mass index (BMI) or BMI and psychiatric disorders.

STUDY RESULTS: High-, medium-, or low-risk controls gained on average 1.32%, 0.42%, and 0.36% more weight per month than patients switching from or within these risk categories (P < .001, P < .001, and P = .003, respectively). High-to-high or high-to-medium switches resulted in a greater weight increase than switching to lower-risk categories (+0.77% and + 0.39% respectively, P < .001). No difference was found between switching medium-to-medium and medium-to-low (P ≈ 1). Switching high-to-low resulted in 10% weight loss after 2 years, with the greatest loss occurring the first 6 months after the switch. Compared with high-risk controls, lower total cholesterol (-0.27 mmol/l, P = .043) in the high-to-low group, and lower glucose (-0.44 mmol/l, P = .032) and systolic blood pressure (-5.50 mmHg, P = .034) in the low-to-low group were found. Polygenic scores were not associated with weight changes in controls or after switching.

CONCLUSION: Psychotropic switches to a lower- or same-risk drug can attenuate weight gain, with only switching high to low resulting in weight loss.

PMID:36156101 | DOI:10.1093/schbul/sbac133

J Occup Environ Med. 2022 Sep 22. doi: 10.1097/JOM.0000000000002705. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess adoption of a pharmacogenomic-enriched comprehensive medication management (PGx + CMM) program in a self-insured employer setting and to better understand medication risks that affect employees.

METHODS: Employees were identified to be at high risk of medication mismanagement and were subsequently provided with a program and process to improve their health. DNA testing, a clinical decision support system, and pharmacists were utilized to identify medication safety and effectiveness issues and to recommend appropriate changes.

RESULTS: 10.6% of the invited employees enrolled in the program. Actionable recommendations were suggested by pharmacists for 85.8% of employees who completed the program, averaging 5.2 recommendations per person.

CONCLUSIONS: Implementation of a PGx + CMM program in a self-insured employer setting is feasible, detects risks in prescription regimens, and offers opportunities to improve medication management and reduce the burden of healthcare expenses.

PMID:36155954 | DOI:10.1097/JOM.0000000000002705

Hum Genomics. 2022 Sep 25;16(1):42. doi: 10.1186/s40246-022-00417-9.

ABSTRACT

BACKGROUND: Pharmacogenomic (PGx) testing has proved its utility and cost-effectiveness for some commonly prescribed cardiovascular disease (CVD) medications. In addition, PGx-guided dosing guidelines are now available for multiple CVD drugs, including clopidogrel, warfarin, and statins. The United Arab Emirates (UAE) population is diverse and multiethnic, with over 150 nationalities residing in the country. PGx-testing is not part of the standard of care in most global healthcare settings, including the UAE healthcare system. The first pharmacogenomic implementation clinical study in CVD has been approved recently, but multiple considerations needed evaluation before commencing. The current report appraises the PGx-clinical implementation procedure and the potential benefits of pursuing PGx-implementation initiatives in the UAE with global implications.

METHODS: Patients prescribed one or more of the following drugs: clopidogrel, atorvastatin, rosuvastatin, and warfarin, were recruited. Genotyping selected genetic variants at genes interacting with the study drugs was performed by real-time PCR.

RESULTS: For the current pilot study, 160 patients were recruited. The genotypes and inferred haplotypes, diplotypes, and predicted phenotypes revealed that 11.9% of the participants were poor CYP2C19 metabolizers, 35% intermediate metabolizers, 28.1% normal metabolizers, and 25% rapid or ultrarapid metabolizers. Notably, 46.9% of our cohort should receive a recommendation to avoid using clopidogrel or consider an alternative medication. Regarding warfarin, only 20% of the participants exhibited reference alleles at VKORC1-1639G > A, CYP2C9*2, and CYP2C9*3, leaving 80% with alternative genotypes at any of the two genes that can be integrated into the warfarin dosing algorithms and can be used whenever the patient receives a warfarin prescription. For statins, 31.5% of patients carried at least one allele at the genotyped SLCO1B1 variant (rs4149056), increasing their risk of developing myopathy. 96% of our cohort received at least one PGx-generated clinical recommendation for the studied drugs.

CONCLUSION: The current pilot analysis verified the feasibility of PGx-testing and the unforeseen high frequencies of patients currently treated with suboptimal drug regimens, which may potentially benefit from PGx testing.

PMID:36154845 | DOI:10.1186/s40246-022-00417-9

Eur Heart J Cardiovasc Pharmacother. 2022 Sep 24:pvac038. doi: 10.1093/ehjcvp/pvac038. Online ahead of print.

NO ABSTRACT

PMID:36153632 | DOI:10.1093/ehjcvp/pvac038

Mol Genet Metab. 2022 Sep 17;137(1-2):210-212. doi: 10.1016/j.ymgme.2022.09.003. Online ahead of print.

NO ABSTRACT

PMID:36152474 | DOI:10.1016/j.ymgme.2022.09.003

Clin Transl Sci. 2022 Sep 24. doi: 10.1111/cts.13422. Online ahead of print.

ABSTRACT

Clinical response of clozapine is closely associated with serum concentration. While tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants vs. noncarriers, both among smokers (-48%; p<0.0001) and nonsmokers (-35%; p=0.028). Smoker patients carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D vs. nonsmoking noncarriers (p<0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in smoker patients carrying NFIB-C and CYP1A-T variants vs. nonsmoking noncarriers (p<0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Smoking patients carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need 3-fold higher doses to prevent risk of clozapine undertreatment. The results suggest that preemptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment resistant schizophrenia.

PMID:36152308 | DOI:10.1111/cts.13422