Pharmgenomics Pers Med. 2021 Dec 14;14:1619-1628. doi: 10.2147/PGPM.S338198. eCollection 2021.

ABSTRACT

PURPOSE: Pharmacogenetic testing is recognized as the major method for the individualized pharmacotherapy in clinical pharmacy practice, but information about the clinical implementation of pharmacogenetic testing in China is limited. The present study aimed to determine the situation of clinical implementation for pharmacogenetic testing in central China.

METHODS: The study is conducted in the department of clinical pharmacy in The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. We collected and analyzed pharmacogenetic testing results from November 1, 2013 to November 2, 2018 in our hospital, which were checked in the electronic medical record system. The main outcome measures were the number and type of pharmacogenetic testing across five years.

RESULTS: A total of 47,265 (56.9% male, mean age = 51.5 years) pharmacogenetic testing results were obtained with an average annual rate of growth of 63.0% across five years. A 50.2% (23,748/47,265) of all the pharmacogenetic testing results were for the determination of cytochrome P450 2C19 (CYP2C19) *2, *3 genotypes, and 41.7% were for the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. The number of departments performing the pharmacogenetic testing was 35, 63, 55, 52, 52 and 39 for 2013-2018, respectively, and the main top five departments were cardiology, psychiatry, ICU, cardiac surgery and intervention.

CONCLUSION: Clinical implementation of pharmacogenetic testing in China is growing rapidly, but the types and implementing departments of pharmacogenetic testing were limited. Our present study reported the real-world implementation modality of pharmacogenomic tests in China. It will help us to understand the testing of pharmacogenetics in China in order to promote the rational development of pharmacogenetics.

PMID:34934339 | PMC:PMC8684419 | DOI:10.2147/PGPM.S338198

Pharmacogenomics J. 2021 Dec 21. doi: 10.1038/s41397-021-00264-2. Online ahead of print.

NO ABSTRACT

PMID:34934177 | DOI:10.1038/s41397-021-00264-2

Drug Metab Dispos. 2021 Dec 21:DMD-AR-2020-000323. doi: 10.1124/dmd.120.000323. Online ahead of print.

ABSTRACT

The prodrug tenofovir alafenamide (TAF) is a first-line antiviral agent for the treatment of chronic hepatitis B infection. TAF activation involves multiple steps, and the first step is an ester hydrolysis reaction catalyzed by hydrolases. This study was to determine the contributions of carboxylesterase 1 (CES1) and cathepsin A (CatA) to TAF hydrolysis in the human liver. Our in vitro incubation studies showed that both CatA and CES1 catalyzed TAF hydrolysis in a pH-dependent manner. At their physiological pH environment, the activity of CatA (pH 5.2) was approximately 1,000-fold higher than that of CES1 (pH 7.2). Given that the hepatic protein expression of CatA was approximately 200-fold lower than that of CES1, the contribution of CatA to TAF hydrolysis in the human liver was estimated to be much greater than that of CES1, which is contrary to the previous perception that CES1 is the primary hepatic enzyme hydrolyzing TAF. The findings were further supported by a TAF incubation study with the CatA inhibitor telaprevir and the CES1 inhibitor bis-(p-nitrophenyl) phosphate. Moreover, an in vitro study revealed that the CES1 variant G143E (rs71647871) is a loss-of-function variant for CES1-mediated TAF hydrolysis. In summary, our results suggest that CatA may play a more important role in the hepatic activation of TAF than CES1. Additionally, TAF activation in the liver could be affected by CES1 genetic variation, but the magnitude of impact appears to be limited due to the major contribution of CatA to hepatic TAF activation. Significance Statement Contrary to the general perception that carboxylesterase 1 (CES1) is the major enzyme responsible for tenofovir alafenamide (TAF) hydrolysis in the human liver, the present study demonstrated that cathepsin A (CatA) may play a more significant role in TAF hepatic hydrolysis. Furthermore, the CES1 variant G143E (rs71647871) was found to be a loss-of-function variant for CES1-mediated TAF hydrolysis.

PMID:34933885 | DOI:10.1124/dmd.120.000323

Am J Hum Genet. 2021 Dec 16:S0002-9297(21)00452-3. doi: 10.1016/j.ajhg.2021.11.021. Online ahead of print.

ABSTRACT

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

PMID:34932938 | DOI:10.1016/j.ajhg.2021.11.021

Int J Biol Markers. 2021 Dec 21:17246008211064915. doi: 10.1177/17246008211064915. Online ahead of print.

ABSTRACT

INTRODUCTION: Disease recurrence after surgery is a crucial predictor of poor prognosis in colorectal cancer, where disseminated disease at the time of intervention can also be observed in localized early-stage cases. We evaluated the ability to predict disease recurrence of miRNAs from two signatures that we have found linked to the presence of colorectal cancer (CL signature) or adenoma (HgA signature) in higher-risk subjects.

METHODS: miRNAs from the signatures were studied longitudinally by quantitative real-time polymerase chain reaction in plasma from 24 patients with resectable colorectal cancer collected at the time of surgery and during scheduled follow-up across 36 months. Patients either showed relapse within 36 months (alive with disease (AWD)), or remained disease-free (no evidence of disease (NED)) for the same period.

RESULTS: Although the signatures did not predict recurrence, expression of the miRNAs from the CL signature decreased 1 year after surgery, and one miRNA of the signature, miR-378a-3p, almost reached significance in the NED subgroup (Wilcoxon signed-rank test: p-value = 0.078). Also, miR-335-5p from the HgA signature was higher in AWD patients before surgery (Kruskal-Wallis test: p-value = 0.019).

CONCLUSIONS: These data, although from a small cohort of patients, support the possible use of miRNAs as non-invasive biomarkers in liquid biopsy-based tests to identify patients at risk of relapse and to monitor them during follow-up.

PMID:34931559 | DOI:10.1177/17246008211064915

J Transl Med. 2021 Dec 20;19(1):520. doi: 10.1186/s12967-021-03192-8.

ABSTRACT

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs' exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal-epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens.

PMID:34930319 | DOI:10.1186/s12967-021-03192-8

Psychiatr Danub. 2021 Winter;33(4):523-531. doi: 10.24869/psyd.2021.523.

ABSTRACT

BACKGROUND: Adverse events (AEs) contribute to poor outcome in patients affected by mental disorders. The aim of this case series is to describe how many antipsychotics-associated serious AEs could have been prevented if we had known in advance the genetic profile of the patient.

SUBJECTS AND METHODS: Data of patients who required the prescription of an antipsychotic drug, with a history of a documented antipsychotics-associated serious AE and who underwent Neuropharmagen® test were retrospectively collected.

RESULTS: Thirty-three subjects were selected for eligibility; two of them were excluded. Twelve subjects (38.7%) showed genetic polymorphisms most likely associated to an increased risk of AE, with pharmacokinetic variations being the most prevalent. Moreover, the 35.5% of the total sample revealed drug-drug interactions (pharmacodynamic/pharmacokinetic) associated with increased risk of AE.

CONCLUSIONS: This case series highlights how pharmacogenetics testing with decision support tools, if applied earlier during the treatment with antipsychotics, could have led to identifying individuals at risk for serious AEs.

PMID:34928900 | DOI:10.24869/psyd.2021.523

Biomed Res Int. 2021 Dec 9;2021:6830560. doi: 10.1155/2021/6830560. eCollection 2021.

ABSTRACT

Aspirin, as one of the most frequently prescribed drugs, can have therapeutic effects on different conditions such as cardiovascular and metabolic disorders and malignancies. The effects of this common cardiovascular drug are exerted through different molecular and cellular pathways. Altered noncoding RNA (ncRNA) expression profiles during aspirin treatments indicate a close relationship between these regulatory molecules and aspirin effects through regulating gene expressions. A better understanding of the molecular networks contributing to aspirin efficacy would help optimize efficient therapies for this very popular drug. This review is aimed at discussing and highlighting the identified interactions between aspirin and ncRNAs and their targeting pathways and better understanding pharmacogenetic responses to aspirin.

PMID:34926688 | PMC:PMC8677408 | DOI:10.1155/2021/6830560

Front Endocrinol (Lausanne). 2021 Dec 1;12:750999. doi: 10.3389/fendo.2021.750999. eCollection 2021.

ABSTRACT

BACKGROUND: To investigate the relationship between different classes of obesity and stroke, we conducted a stratified Mendelian randomization (MR) study.

METHODS: The body mass index (BMI) data of 263,407 Europeans with three classes of obesity (obesity class I, 30 kg/m2 ≤ BMI < 35 kg/m2; obesity class II, 35 kg/m2 ≤ BMI < 40 kg/m2; obesity class III, 40 kg/m2 ≤ BMI) were extracted from the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary-level data of stroke and its subtypes [ischemic stroke (IS) and intracerebral hemorrhage (ICH)] were obtained from the genome-wide association study (GWAS) meta-analysis, which was performed by the MEGASTROKE consortium. MR methods were used to identify the causal relationships.

RESULTS: The MR analysis revealed that both obesity class I [odds ratio (OR) = 1.08, 95% CI: 1.05-1.12, p = 1.0 × 10-5] and obesity class II (OR = 1.06, 95% CI: 1.03-1.09, p = 1 × 10-4) were significantly positively related to IS, while obesity class III was not (OR = 1.01, 95% CI: 0.96-1.06, p = 0.65). In contrast to IS, there was no class of obesity associated with ICH risk. Further examination of the relationship between obesity classification and IS subtypes revealed that certain degrees of obesity were related to large artery stroke (LAS) (OR = 1.14, 95% CI: 1.04-1.24, p = 2.8 × 10-3 for class I; OR = 1.08, 95% CI: 1.01-1.16, p = 0.002 for class II) and cardioembolic stroke (CES) (OR = 1.11, 95% CI: 1.02-1.20, p = 0.02 for class I; OR = 1.08, 95% CI: 1.02-1.15, p = 0.007 for class II).

CONCLUSIONS: A higher risk of IS, but not ICH, could be linked to obesity classes I and II. A strong association between LAS and CES and obesity was observed among all IS subtypes in the obese population.

PMID:34925231 | PMC:PMC8671740 | DOI:10.3389/fendo.2021.750999

Front Pharmacol. 2021 Dec 2;12:784712. doi: 10.3389/fphar.2021.784712. eCollection 2021.

ABSTRACT

Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author's name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11-18.35) and 16.35 (95% CI 10.20-26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65-24.27) and early neutropenia (OR 15.85; 95% CI 8.80-28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99-708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.

PMID:34925040 | PMC:PMC8675242 | DOI:10.3389/fphar.2021.784712

Dig Liver Dis. 2021 Sep 2:S1590-8658(21)00214-0. doi: 10.1016/j.dld.2021.04.029. Online ahead of print.

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.

PMID:34924319 | DOI:10.1016/j.dld.2021.04.029

Nutr Metab Cardiovasc Dis. 2021 Sep 9:S0939-4753(21)00221-0. doi: 10.1016/j.numecd.2021.04.028. Online ahead of print.

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.

PMID:34924246 | DOI:10.1016/j.numecd.2021.04.028

Eur Neuropsychopharmacol. 2021 Dec 16;56:39-49. doi: 10.1016/j.euroneuro.2021.12.003. Online ahead of print.

ABSTRACT

Suicide claims over 800,000 deaths worldwide, making it a serious public health problem. The etiopathophysiology of suicide remains unclear and is highly complex, and postmortem gene expression studies can offer insights into the molecular biological mechanism underlying suicide. In the current study, we conducted a meta-analysis of postmortem brain gene expression in relation to suicide. We identified five gene expression datasets for postmortem orbitofrontal, prefrontal, or dorsolateral prefrontal cortical brain regions from the Gene Expression Omnibus repository. After quality control, the total sample size was 380 (141 suicide deaths and 239 deaths from other causes). We performed the analyses using two meta-analytic approaches. We further performed pathway and cell-set enrichment analyses. We found reduced expression of the KCNJ2 (Potassium Inwardly Rectifying Channel Subfamily J Member 2), A2M (Alpha-2-Macroglobulin), AGT (Angiotensinogen), PMP2 (Peripheral Myelin Protein 2), and VEZF1 (Vascular Endothelial Zinc Finger 1) genes (FDR p<0.05). Our findings support the involvement of astrocytes, stress response, immune system, and microglia in suicide. These findings will require further validation in additional large datasets.

PMID:34923210 | DOI:10.1016/j.euroneuro.2021.12.003

Therapie. 2021 Nov 25:S0040-5957(21)00241-9. doi: 10.1016/j.therap.2021.11.003. Online ahead of print.

ABSTRACT

The discovery of molecular alterations involved in oncogenesis is evolving rapidly and has led to the development of new innovative targeted therapies in oncology. High-throughput sequencing techniques help to identify genomic targets and to provide predictive molecular biomarkers of response to guide alternative therapeutic strategies. Besides the emergence of these theranostic markers for the new targeted treatments, pharmacogenetic markers (corresponding to genetic variants existing in the constitutional DNA, i.e., the host genome) can help to optimize the use of chemotherapy. In this review, we present the current clinical applications of constitutional PG and the recent concepts and advances in pharmacogenomics, a rapidly evolving field that focuses on various molecular alterations identified on constitutional or somatic (tumor) genome.

PMID:34922740 | DOI:10.1016/j.therap.2021.11.003

Sci Rep. 2021 Dec 17;11(1):24206. doi: 10.1038/s41598-021-03624-x.

ABSTRACT

MYB proteins are highly conserved DNA-binding domains (DBD) and mutations in MYB oncoproteins have been reported to cause aberrant and augmented cancer progression. Identification of MYB molecular biomarkers predictive of cancer progression can be used for improving cancer management. To address this, a biomarker discovery pipeline was employed in investigating deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in predicting damaging and potential alterations on the properties of proteins. The nsSNP of the MYB family; MYB, MYBL1, and MYBL2 was extracted from the NCBI database. Five in silico tools (PROVEAN, SIFT, PolyPhen-2, SNPs&GO and PhD-SNP) were utilized to investigate the outcomes of nsSNPs. A total of 45 nsSNPs were predicted as high-risk and damaging, and were subjected to PMut and I-Mutant 2.0 for protein stability analysis. This resulted in 32 nsSNPs with decreased stability with a DDG score lower than - 0.5, indicating damaging effect. G111S, N183S, G122S, and S178C located within the helix-turn-helix (HTH) domain were predicted to be conserved, further posttranslational modifications and 3-D protein analysis indicated these nsSNPs to shift DNA-binding specificity of the protein thus altering the protein function. Findings from this study would help in the field of pharmacogenomic and cancer therapy towards better intervention and management of cancer.

PMID:34921182 | DOI:10.1038/s41598-021-03624-x

Stud Health Technol Inform. 2021 Dec 15;284:203-208. doi: 10.3233/SHTI210705.

ABSTRACT

This paper provides a discourse based upon the key development of nursing in response to the emerging 4Ds of health technology re-design. Building informatics capability among health professionals is a workforce issue necessitated through the increasing prevalence of information technology and digitization of healthcare affecting the entire health workforce, specifically front-line nurses. The key concepts will be explored of Digitization, Distribution, Disruption and Diversity, a framework recognising the tsunami of technology such as Big Data analytics, comprehensive decision support systems for nursing, nanobots, robotics, and pharmacogenomics and the impact these have upon the nursing workforce.

PMID:34920509 | DOI:10.3233/SHTI210705

Eur Heart J. 2021 Dec 16:ehab836. doi: 10.1093/eurheartj/ehab836. Online ahead of print.

ABSTRACT

AIMS: Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS.

METHODS AND RESULTS: We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments.

CONCLUSION: In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS.

STUDY REGISTRATION NUMBER: This study is registered in PROSPERO (CRD42021258603).

KEY QUESTION: A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored.

KEY FINDING: In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality.

TAKE HOME MESSAGE: A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.

PMID:34918066 | DOI:10.1093/eurheartj/ehab836

Front Pharmacol. 2021 Nov 30;12:726784. doi: 10.3389/fphar.2021.726784. eCollection 2021.

ABSTRACT

Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

PMID:34916931 | PMC:PMC8669916 | DOI:10.3389/fphar.2021.726784

Pharmgenomics Pers Med. 2021 Dec 9;14:1603-1617. doi: 10.2147/PGPM.S337147. eCollection 2021.

ABSTRACT

Pharmacogenomic screening can identify patients with gene variants that predispose them to the development of severe toxicity from fluoropyrimidine (FP) chemotherapy. Deficiency of the critical metabolic enzyme dihydropyrimidine dehydrogenase (DPD) leads to excessive toxicity on exposure to fluoropyrimidine chemotherapy. This can result in hospitalisation, intensive care admissions and even death. Upfront screening of the gene that encodes for DPD (DPYD) has recently been implemented in regions throughout Europe and the United Kingdom. Current screening evaluates DPYD variants that are well described within Caucasian patient populations and provides genotyped-guided dose adjustment recommendations based upon the presence of these variants. This article reviews the differences in DPYD gene variants within non-Caucasian populations compared to Caucasian populations, with regard to the implications for clinical tolerance of fluoropyrimidine chemotherapies and genotype guided dose adjustment guidelines.

PMID:34916829 | PMC:PMC8668257 | DOI:10.2147/PGPM.S337147

Pharmacogenomics. 2021 Dec 16. doi: 10.2217/pgs-2021-0131. Online ahead of print.

ABSTRACT

Introduction: Pharmacogenomic testing can indicate which drugs may have limited therapeutic action or lead to adverse effects, hence guiding rational and safe prescribing. However, in the UK and other countries, there are still significant barriers to implementation of testing in primary care. Objective: This systematic review presents the barriers and enablers to the implementation of pharmacogenomics in primary care setting. Materials & methods: MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched through to July 2020 for studies that reported primary qualitative data of primary care professionals and patient views. Following screening, data extraction and quality assessment, data synthesis was undertaken using meta-aggregation based on the theoretical domain's framework (TDF). Confidence in the synthesized findings relating to credibility and dependability was established using CONQual. Eligible papers were categorized into six TDF domains - knowledge; social and professional roles; behavioral regulation; beliefs and consequences; environmental context and resources; and social influences. Results: From 1669 citations, eighteen eligible studies were identified across seven countries, with a sample size of 504 participants including both primary care professionals and patients. From the data, 15 synthesized statements, all with moderate CONQual rating emerged. These categories range from knowledge, awareness among Primary Care Physicians and patients, professional relationships, negative impact of PGx, belief that PGx can reduce adverse drug reactions, clinical evidence, cost-effectiveness, informatics, reporting issues and social issues. Conclusion: Through use of TDF, fifteen synthesized statements provide policymakers with valuable recommendations for the implementation of pharmacogenomics in primary care. In preparation, policymakers need to consider the introduction of effective educational strategies for both PCPs and patients to raise knowledge, awareness, and engagement. The actual introduction of PGx will require reorganization with decision support tools to aid use of PGx in primary care, with a clear delegation of roles and responsibilities between general professionals and pharmacists supplemented by a local pool of experts. Further policy makers need to address the cost effectiveness of pharmacogenomics and having appropriate infrastructure supporting testing and interpretation including informatic solutions for utilizing pharmacogenomic results.

PMID:34911350 | DOI:10.2217/pgs-2021-0131