PLoS One. 2022 Jan 28;17(1):e0263137. doi: 10.1371/journal.pone.0263137. eCollection 2022.

ABSTRACT

It is well documented that drug responses are related to Absorption, Distribution, Metabolism, and Excretion (ADME) characteristics of individual patients. Several studies have identified genetic variability in pharmacogenes, that are either directly responsible for or are associated with ADME, giving rise to individualized treatments. Our objective was to provide a comprehensive overview of pharmacogenetic variation in the Saudi population. We mined next generation sequencing (NGS) data from 11,889 unrelated Saudi nationals, to determine the presence and frequencies of known functional SNP variants in 8 clinically relevant pharmacogenes (CYP2C9, CYP2C19, CYP3A5, CYP4F2, VKORC1, DPYD, TPMT and NUDT15), recommended by the Clinical Pharmacogenetics Implementation Consortium (CPIC), and collectively identified 82 such star alleles. Functionally significant pharmacogenetic variants were prevalent especially in CYP genes (excluding CYP3A5), with 10-44.4% of variants predicted to be inactive or to have decreased activity. In CYP3A5, inactive alleles (87.5%) were the most common. Only 1.8%, 0.7% and 0.7% of NUDT15, TPMT and DPYD variants respectively, were predicted to affect gene activity. In contrast, VKORC1 was found functionally, to be highly polymorphic with 53.7% of Saudi individuals harboring variants predicted to result in decreased activity and 31.3% having variants leading to increased metabolic activity. Furthermore, among the 8 pharmacogenes studied, we detected six rare variants with an aggregated frequency of 1.1%, that among several other ethnicities, were uniquely found in Saudi population. Similarly, within our cohort, the 8 pharmacogenes yielded forty-six novel variants predicted to be deleterious. Based upon our findings, 99.2% of individuals from the Saudi population carry at least one actionable pharmacogenetic variant.

PMID:35089958 | DOI:10.1371/journal.pone.0263137

Front Pharmacol. 2022 Jan 11;12:833000. doi: 10.3389/fphar.2021.833000. eCollection 2021.

NO ABSTRACT

PMID:35087412 | PMC:PMC8786742 | DOI:10.3389/fphar.2021.833000

Ann Oncol. 2022 Jan 24:S0923-7534(22)00014-X. doi: 10.1016/j.annonc.2022.01.005. Online ahead of print.

NO ABSTRACT

PMID:35086737 | DOI:10.1016/j.annonc.2022.01.005

Pediatr Nephrol. 2022 Jan 27. doi: 10.1007/s00467-021-05415-y. Online ahead of print.

NO ABSTRACT

PMID:35084566 | DOI:10.1007/s00467-021-05415-y

Pharmacogenomics. 2022 Jan 27. doi: 10.2217/pgs-2021-0125. Online ahead of print.

ABSTRACT

Aim: To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Patients & methods: Prescription frequencies for 65 medications with actionable PGx recommendations were collected in 215 percutaneous coronary intervention (PCI) and 131 allogeneic hematopoietic cell transplant (allo-HCT) patients. A simulation projected the number of PGx-guided prescribing opportunities. Results: In PCI and allo-HCT patients, respectively, 66.5 and 90.1% were prescribed at least one medication with actionable PGx prescribing recommendations. Simulations projected 26.5 and 41.2 total PGx-guided prescribing opportunities per 100 PCI and allo-HCT patients, respectively, if multigene PGx results were available. Conclusion: A multigene PGx testing strategy offers potential to optimize medication prescribing beyond clopidogrel and tacrolimus in PCI and allo-HCT patients.

PMID:35083934 | DOI:10.2217/pgs-2021-0125

Pharmacogenomics. 2022 Jan 27. doi: 10.2217/pgs-2021-0149. Online ahead of print.

ABSTRACT

The discovery of haplotypes with unknown or uncertain function in the CYP2D6 pharmacogene is outpacing the capabilities of traditional in vitro and in vivo approaches to characterize their function. This challenge will undoubtedly grow as pharmacogenomic research becomes more inclusive of globally diverse populations. As accurate phenotypic assignment is paramount to the utility of pharmacogenomics, high-throughput technologies are needed for this complex pharmacogene. We describe the evolving landscape of innovative approaches to assign function to CYP2D6 haplotypes and possibilities for adopting these technologies into cohesive processes. Promising approaches include ADME optimized prediction frameworks, machine learning algorithms, deep mutational scanning and phenoconversion predictions. Implementing these approaches will lead to improved personalization of treatment for patients.

PMID:35083931 | DOI:10.2217/pgs-2021-0149

Pharmacogenomics. 2022 Jan 27. doi: 10.2217/pgs-2021-0120. Online ahead of print.

ABSTRACT

Aim: To develop and assess an augmented reality tool for pharmacogenomics (PGx) education based on artificial intelligence. Materials & methods: A HoloLens application was developed using feedback from three clinical PGx-trained pharmacists. 15 Participants independently reviewed the application and assessed usability using the system usability scale (SUS). Results & conclusion: Eighteen different frames were developed. Each video module was 2-3 min for the education. The application included textual information and 3D structures of PGx concepts. The mean SUS score for 15 participants (11 pharmacy students and four pharmacists) was 83, with a standard deviation of 6.6. Results suggest that PGxKnow has the potential to bridge the gap in PGx education, further widespread utilization of PGx and boost its impact on precision medicine.

PMID:35083917 | DOI:10.2217/pgs-2021-0120

Pharmacogenomics. 2022 Jan 27. doi: 10.2217/pgs-2021-0135. Online ahead of print.

ABSTRACT

Aim: Sertraline is a CYP2C19 substrate commonly prescribed to children with anxiety. Materials & methods: This medical record review examined dosing trends and treatment discontinuation in children prescribed sertraline with documented CYP2C19 genotypes. Variables collected included age, weight, diagnosis, concomitant medications, initial sertraline dose, dose changes and CYP2C19 genotypes. Results: A total of 90 individuals (average age: 10.5 years; 40% female) were included. Nearly 80% were prescribed sertraline for anxiety. Initial weight-adjusted doses were similar, but mean weight-adjusted doses of sertraline were 65% higher in increased metabolizers (1.5 mg/kg/day) compared with normal metabolizers (0.91 mg/kg/day; p = 0.067) at the second dose change. Conclusion: While all children started at a similar sertraline dose, different trends in prescribed doses were observed across CYP2C19 genotypes at subsequent dose changes.

PMID:35083916 | DOI:10.2217/pgs-2021-0135

Br J Clin Pharmacol. 2022 Jan 26. doi: 10.1111/bcp.15245. Online ahead of print.

ABSTRACT

OBJECTIVE: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications.

METHODS AND ANALYSIS: 69,185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40 to 79 years at first prescription; treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5mmol/L) at baseline, plus treatment discontinuation.

RESULTS: 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol, vs. 41.7% of those with functioning SLCO1B1 (Odds Ratio 1.31: 95% Confidence Intervals 1.1 to 1.55, p=0.001). Fewer males had high cholesterol, and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (Hazard Ratio 1.19: 95%CI 1.03 to 1.37, p=0.01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3: 95%CI 1.08 to 1.56; p=0.006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year.

CONCLUSIONS: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.

PMID:35083771 | DOI:10.1111/bcp.15245

Br J Dermatol. 2022 Jan 26. doi: 10.1111/bjd.21030. Online ahead of print.

NO ABSTRACT

PMID:35083741 | DOI:10.1111/bjd.21030

Cancer Chemother Pharmacol. 2022 Jan 27. doi: 10.1007/s00280-021-04389-w. Online ahead of print.

ABSTRACT

PURPOSE: Genetic variants may influence the pharmacokinetics and pharmacodynamics (PKPD) of cyclophosphamide (CY). CY plays a critical role in conditioning chemotherapy for hematopoietic cell transplantation (HCT), but its use is limited by toxicity. We explored the effect of genetic variants, potentially affecting PKPD of CY, and outcomes after HCT.

METHODS: This observational pharmacogenomic study included 85 adults with hematologic malignancies who received reduced intensity conditioning with CY, fludarabine, and total body irradiation. We collected recipient DNA prior to HCT and evaluated 97 candidate variants in 66 genes and 3 metabolism phenotypes potentially involved in PKPD pathways of CY. In multivariable analysis we investigated the association between the genotypes and four clinical outcomes: Day 180 non-relapse mortality (NRM) and day 180 overall survival (OS), acute graft-versus-host-disease (aGVHD) grades 2-4, and engraftment. p values were not adjusted for multiple testing.

RESULTS: The median recipient age was 63 years (range 21-75). Acute myeloid leukemia was the most common diagnosis (34%; n = 29). In multivariable analysis adjusted for exposure to phosphoramide mustard, the final active metabolite of CY, we identified 6 variants in 6 genes associated with at least one of the clinical outcomes. An ABCC4 variant (rs9561778) was associated with poor Day 180 NRM (p < 0.01), MUTYH variant (rs3219484) with higher Day 180 NRM and aGVHD (both p < 0.01), and SYNE1 variant (rs4331993) with better Day 180 OS and engraftment (both p ≤ 0.01).

CONCLUSION: The present study suggests that genetic variants influencing the PKPD of CY may help identify patients at risk for inferior outcomes after HCT using CY-based reduced-intensity conditioning.

PMID:35083501 | DOI:10.1007/s00280-021-04389-w

Biomed Res Int. 2022 Jan 17;2022:6116003. doi: 10.1155/2022/6116003. eCollection 2022.

ABSTRACT

To prospect an isozyme-specific, effective inhibitor against the physiologically-crucial enzyme phosphodiesterase 1 (PDE1), phytochemicals from Pistacia integerrima galls were screened. The chloroform fraction of gall extract was subjected to column chromatographic which led to the isolation of compound 1, elucidated to be 5-hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (a flavone). In vitro and in silico PDE1 inhibitory activity of the compound 1 was investigated. EDTA, a known PDE1 inhibitor, was used as the reference. The flavone exhibited in vitro attenuation towards snake venom PDE1. IC50 response was superior to the standard chelator. An in silico molecular docking study was carried out using 3D structure of PDE1 to study the binding interactions of compound 1. The docking study predicted that flavone had a lower binding affinity (-7.6 kcal/mol) and total energy (-95 kcal/mol) score compared to EDTA. The minimal energy associated with the ligand-protein complex implied that isolated compound 1 can serve as a therapeutic agent against PDE1 enzyme-provoked ailments like asthma, hypertension, schizophrenia, and erectile dysfunction.

PMID:35083331 | PMC:PMC8786535 | DOI:10.1155/2022/6116003

J Anal Methods Chem. 2022 Jan 17;2022:5952436. doi: 10.1155/2022/5952436. eCollection 2022.

ABSTRACT

Mice are the most frequently used animals in pharmacokinetic studies; however, collecting series of blood samples from mice is difficult because of their small sizes and tiny vessels. In addition, due to the small sample size, it is problematic to perform high required quantification. Thus, present work aims to find an effective strategy for overcoming these challenges using trans-resveratrol as a tool drug. Based on the idea of a joint technology, the capillary microsampling (CMS) was chosen for blood sample collection from mice after delivery of trans-resveratrol (150 mg/kg) by gavage, and a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of trans-resveratrol and its main metabolites. All the mouse blood samples were exactly collected by CMS without obvious deviation. This provided credible samples for subsequent quantitative analysis. The HPLC-MS/MS method was found to be sensitive, accurate, and repeatable, and the pharmacokinetic parameters for all analytes were comparable with those reported in previous studies. However, the present joint technology offers the advantages of less animal damage, easy for sample preparation, and improved reliability. It has overcome some of the major limitations revealed in previous pharmacokinetic studies in mice and therefore provides a more effective option for future studies.

PMID:35083093 | PMC:PMC8786553 | DOI:10.1155/2022/5952436

Pharmgenomics Pers Med. 2022 Jan 20;15:29-43. doi: 10.2147/PGPM.S338287. eCollection 2022.

ABSTRACT

BACKGROUND: Generally, many individual factors can affect the clinical application of drugs, of which genetic factors contribute more than 20%. Ticagrelor is a new class of receptor inhibitors receptor antagonist of P2Y12 and is used as an antiplatelet agents. But it is not affected by the influence of CYP2C19 polymorphism. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of ticagrelor in the antiplatelet efficacy and safety, through pharmacogenomics research.

METHODS: Whole-exome sequencing (WES) was performed in 100 patients after PCI with ticagrelor treatment. Clinical characteristics and WES of patients were used to performed genome-wide association analysis (GWAS), region-based tests of rare DNA variant to find the influencing factors of antiplatelet effect to ticagrelor and bleeding events. Co-expression, protein-protein interaction (PPI) network and pathway enrichment analysis were then used to find possible genetic mechanisms. Atlas of GWAS (https://atlas.ctglab.nl/) were used for external data validation.

RESULTS: DNAH17, PGS1 and ABCA1 as the potential variant genes are associated with the expected antiplatelet effect to ticagrelor. The affected pathways may include the synthesis and metabolism of lipoprotein cholesterol and the catabolic process of pyrimidine-containing compound (GO:0072529). Age, sex and PLT were found may be potential factors for ticagrelor bleeding events.

CONCLUSION: We systematically identified new genetic variants and some risk factors for reduced efficacy of ticagrelor and highlighted related genes that may be involved in antiplatelet effects and bleeding event of ticagrelor. Our results enhance the understanding of the absorption and metabolic mechanisms that influence antiplatelet response to ticagrelor treatment.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03161002. First Posted: May 19, 2017. https://clinicaltrials.gov/ct2/show/study/NCT03161002.

PMID:35082514 | PMC:PMC8786390 | DOI:10.2147/PGPM.S338287

J Clin Pharmacol. 2022 Jan 24. doi: 10.1002/jcph.2032. Online ahead of print.

ABSTRACT

Use of polypharmacy has become significantly more common over the past two decades, increasing the risk of drug-drug interactions and adverse drug reactions. Pharmacogenomic (PGx) assays have the purported benefit of being able to predict an individual's response to a specific medication based on genetic markers, which may facilitate the development of optimized medication regimens for patients prescribed polypharmacy. This 12-week pilot study examined the impact of the PGx results on the clinical management of Veterans who were prescribed psychiatric polypharmacy. Psychiatric medication providers were given access to the PGx assay results, including notification of drug-drug-gene interactions computed from an algorithm decision tool, to assist with medication management decisions. Veteran outpatients (N = 53) prescribed polypharmacy (Mean = 13.15 medications) were enrolled into the study. In 90.9% of cases, providers changed medications at baseline, with 83% of provider indicating they changed their original medication plan based on PGx results. Clinical improvement over the 12-week treatment phase was seen in depression (F(1.63, 45) = 5.45, p = .01, η2 = .11) and mental health quality of life (F(2, 45) = 4.16, p < .05, η2 = .16). Adverse drug effects were unchanged or improved over time. Rates of polypharmacy remained unchanged. Results suggest that the medication changes based on the PGx assay results may be beneficial in a complex patient population prescribed polypharmacy. Trial Registration: ClinicalTrials.gov Identifier: NCT03468309 This article is protected by copyright. All rights reserved.

PMID:35075665 | DOI:10.1002/jcph.2032

Arch Dis Child. 2022 Jan 24:archdischild-2021-322396. doi: 10.1136/archdischild-2021-322396. Online ahead of print.

ABSTRACT

BACKGROUND: Evidence supporting personalised treatment for asthma based on an individual's genetics is mounting. The views of children and young people (CYP), parents and healthcare professionals (HCPs) about this evolution of clinical care are not known.

METHODS: A pilot prospective questionnaire-based study was undertaken of CYP with asthma, their parents and HCPs at a secondary/tertiary children's hospital in the UK.

RESULTS: Fifty-nine questionnaires were distributed and 50 returned (response rate 84.7%), comprising 26 CYP (10 were 5-11 years, 11 were 12-15 years and 5 were 16-18 years old), 13 parents and 11 HCPs. For all types of data, personal information was ranked as the 'most important' (n=19, 47.5%) and 'most private' (n=16, 40%), but with considerable variation across groups. Within health data, allergies were rated as 'most important' (n=12, 30.8%), and mental health records the 'most private' (n=21, 53.8%), again with variation across groups. A 'personalised genetic asthma plan' was acceptable to the majority overall (n=40, 80.0%). With regard to sharing CYP's genetic data, 23 (46%) of participants were happy for unconditional sharing between HCPs, and 23 (46%) agreed to sharing solely in relation to the CYP's asthma management. Forty-two (84.0%) of participants felt CYP should be informed about genetic data being shared, and the majority felt this should commence by 12 years of age.

CONCLUSION: The use of genetic information to guide management of asthma in CYP is largely acceptable to CYP, parents/guardians and HCPs. However, there are key differences between the opinions of CYP, parents and HCPs.

PMID:35074833 | DOI:10.1136/archdischild-2021-322396

Ann Fam Med. 2022 Jan-Feb;20(1):88. doi: 10.1370/afm.2764.

NO ABSTRACT

PMID:35074774 | DOI:10.1370/afm.2764

Pharmacology. 2022 Jan 24:1-11. doi: 10.1159/000521531. Online ahead of print.

ABSTRACT

INTRODUCTION: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12-20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF).

METHODS: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy - high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA).

RESULTS: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA.

CONCLUSION: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

PMID:35073541 | DOI:10.1159/000521531

PLoS One. 2022 Jan 24;17(1):e0262545. doi: 10.1371/journal.pone.0262545. eCollection 2022.

ABSTRACT

Insight into the metabolic biosignature of tuberculosis (TB) may inform clinical care, reduce adverse effects, and facilitate metabolism-informed therapeutic development. However, studies often yield inconsistent findings regarding the metabolic profiles of TB. Herein, we conducted an untargeted metabolomics study using plasma from 63 Korean TB patients and 50 controls. Metabolic features were integrated with the data of another cohort from China (35 TB patients and 35 controls) for a global functional meta-analysis. Specifically, all features were matched to a known biological network to identify potential endogenous metabolites. Next, a pathway-level gene set enrichment analysis-based analysis was conducted for each study and the resulting p-values from the pathways of two studies were combined. The meta-analysis revealed both known metabolic alterations and novel processes. For instance, retinol metabolism and cholecalciferol metabolism, which are associated with TB risk and outcome, were altered in plasma from TB patients; proinflammatory lipid mediators were significantly enriched. Furthermore, metabolic processes linked to the innate immune responses and possible interactions between the host and the bacillus showed altered signals. In conclusion, our proof-of-concept study indicated that a pathway-level meta-analysis directly from metabolic features enables accurate interpretation of TB molecular profiles.

PMID:35073339 | DOI:10.1371/journal.pone.0262545

Clin Transl Allergy. 2022 Jan 14;12(1):e12098. doi: 10.1002/clt2.12098. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Several type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA) genotypes. However, pre-stored HLA information obtained from other clinical workups has not been used to prevent ADRs. We aimed to simulate the preemptive use of pre-stored HLA information in electronic medical records to evaluate whether this information can prevent ADRs.

METHODS: We analyzed the incidence and the risk of ADRs for selected HLA alleles (HLA-B*57:01, HLA-B*58:01, HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*13:01, HLA-B*59:01, and HLA-A*32:01) and seven drugs (abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin) using pre-stored HLA information of transplant patients based on the Pharmacogenomics Knowledge Base guidelines and experts' consensus.

RESULTS: Among 11,988 HLA-tested transplant patients, 4092 (34.1%) had high-risk HLA alleles, 4583 (38.2%) were prescribed risk drugs, and 580 (4.8%) experienced type B ADRs. Patients with HLA-B*58:01 had a significantly higher incidence of type B ADR and SCARs associated with allopurinol use than that of patients without HLA-B*58:01 (17.2% vs. 11.9%, odds ratio [OR] 1.53 [95% confidence interval {CI} 1.09-2.13], p = 0.001, 2.3% versus 0.3%, OR 7.13 [95% CI 2.19-22.69], p < 0.001). Higher risks of type B ADR and SCARs were observed in patients taking carbamazepine or oxcarbazepine if they had one of HLA-A*31:01, HLA-B*15:02, or HLA-B*15:11 alleles. Vancomycin and dapsone use in HLA-A*32:01 and HLA-B*13:01 carriers, respectively, showed trends toward increased risk of type B ADRs.

CONCLUSION: Utilization of pre-stored HLA data can prevent type B ADRs including SCARs by screening high-risk patients.

PMID:35070271 | PMC:PMC8760506 | DOI:10.1002/clt2.12098