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  1. 01Comprehensive Review of Knee Osteoarthritis Pharmacological Treatment and the Latest Professional Societies' Guidelines.Osteoarthritis is the most common musculoskeletal progressive disease, with the knee as the most commonly affected joint in the human body. While several new medications are still under research, many symptomatic therapy options, such as analgesics (opioid and non-opioid), nonsteroid anti-inflammatory drugs, symptomatic slow-acting drugs in osteoarthritis, and preparations for topical administration, are being used, with a diverse clinical response and inconsistent conclusions across various professional societies guidelines. The concept of pharmacogenomic-guided therapy, which lies on principles of the right medication for the right patient in the right dose at the right time, can significantly increase the patient's response to symptom relief therapy in knee osteoarthritis. Corticosteroid intra-articular injections and hyaluronic acid injections provoke numerous discussions and disagreements among different guidelines, even though they are currently used in daily clinical practice. B
  2. 02Pharmacogenetics Guidelines: Overview and Comparison of the DPWG, CPIC, CPNDS, and RNPGx Guidelines.Many studies have shown that the efficacy and risk of side effects of drug treatment is influenced by genetic variants. Evidence based guidelines are essential for implementing pharmacogenetic knowledge in daily clinical practice to optimize pharmacotherapy of individual patients. A literature search was performed to select committees developing guidelines with recommendations being published in English. The Dutch Pharmacogenetics Working Group (DPWG), the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), and the French National Network (Réseau) of Pharmacogenetics (RNPGx) were selected. Their guidelines were compared with regard to the methodology of development, translation of genotypes to predicted phenotypes, pharmacotherapeutic recommendations and recommendations on genotyping. A detailed overview of all recommendations for gene-drug combinations is given. The committees have similar methodologies of guidelin
  3. 03Effect of pharmacogenomics testing guiding on clinical outcomes in major depressive disorder: a systematic review and meta-analysis of RCT.Background Pharmacogenomic testing guided treatment have been developed to guide drug selection or conversion in major depressive disorder patients. Whether patients benefit from pharmacogenetic testing remains unclear. We aim to evaluates the effect of pharmacogenomic testing guiding on clinical outcomes of major depressive disorder. Methods Pubmed, Embase, and Cochrane Library of Clinical Trials were searched from inception until August 2022. Key terms included pharmacogenomic and antidepressive. Odds ratios (RR) with 95% confidence intervals (95%CIs) were calculated using fixed-effects model for low or moderate heterogeneity or random-effects model for high heterogeneity. Results Eleven studies (5347 patients) were included. Compared with usual group, pharmacogenomic testing guided group was associated with an increased response rate at week 8 (OR 1.32, 95%CI 1.15-1.53, 8 studies, 4328 participants) and week 12 (OR 1.36, 95%CI 1.15-1.62, 4 studies, 2814 participants). Similarly, gui
  4. 04Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study.Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR; ≥ 5 drinks for men, ≥4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N = 1083 European ancestry participants). Single nucleotide po
  5. 05Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines.5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as
  6. 06Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review.Background Medicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes. Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known. Methods The first clinically-focused systematic review on the emerging medical application of cannabis across all major psychiatric disorders was conducted. Current evidence regarding whole plant formulations and plant-derived cannabinoid isolates in mood, anxiety, sleep, psychotic disorders and attention deficit/hyperactivity disorder (ADHD) is discussed; while also detailing clinical prescription considerations (including pharmacogenomics), occupational and public health elements, and future research recommendations. The systematic review of the literature was conducted during 2019, assessing the data fr
  7. 07An Analysis of Pharmacogenomic-Guided Pathways and Their Effect on Medication Changes and Hospital Admissions: A Systematic Review and Meta-Analysis.Ninety-five percent of the population are estimated to carry at least one genetic variant that is discordant with at least one medication. Pharmacogenomic (PGx) testing has the potential to identify patients with genetic variants that puts them at risk of adverse drug reactions and sub-optimal therapy. Predicting a patient's response to medications could support the safe management of medications and reduce hospitalization. These benefits can only be realized if prescribing clinicians make the medication changes prompted by PGx test results. This review examines the current evidence on the impact PGx testing has on hospital admissions and whether it prompts medication changes. A systematic search was performed in three databases (Medline, CINAHL and EMBASE) to search all the relevant studies published up to the year 2020, comparing hospitalization rates and medication changes amongst PGx tested patients with patients receiving treatment-as-usual (TAU). Data extracted from full texts we
  8. 08Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process.The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
  9. 09Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature.Objective Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. Methods A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. Results We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated fa
  10. 10Incidence of Exposure of Patients in the United States to Multiple Drugs for Which Pharmacogenomic Guidelines Are Available.Pre-emptive pharmacogenomic (PGx) testing of a panel of genes may be easier to implement and more cost-effective than reactive pharmacogenomic testing if a sufficient number of medications are covered by a single test and future medication exposure can be anticipated. We analysed the incidence of exposure of individual patients in the United States to multiple drugs for which pharmacogenomic guidelines are available (PGx drugs) within a selected four-year period (2009-2012) in order to identify and quantify the incidence of pharmacotherapy in a nation-wide patient population that could be impacted by pre-emptive PGx testing based on currently available clinical guidelines. In total, 73 024 095 patient records from private insurance, Medicare Supplemental and Medicaid were included. Patients enrolled in Medicare Supplemental age > = 65 or Medicaid age 40-64 had the highest incidence of PGx drug use, with approximately half of the patients receiving at least one PGx drug during the 4 yea
  11. 11Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response: Meta-analysis of three treatment cohorts.There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p
  12. 12Implementation of next generation sequencing into pediatric hematology-oncology practice: moving beyond actionable alterations.Background Molecular characterization has the potential to advance the management of pediatric cancer and high-risk hematologic disease. The clinical integration of genome sequencing into standard clinical practice has been limited and the potential utility of genome sequencing to identify clinically impactful information beyond targetable alterations has been underestimated. Methods The Precision in Pediatric Sequencing (PIPseq) Program at Columbia University Medical Center instituted prospective clinical next generation sequencing (NGS) for pediatric cancer and hematologic disorders at risk for treatment failure. We performed cancer whole exome sequencing (WES) of patient-matched tumor-normal samples and RNA sequencing (RNA-seq) of tumor to identify sequence variants, fusion transcripts, relative gene expression, and copy number variation (CNV). A directed cancer gene panel assay was used when sample adequacy was a concern. Constitutional WES of patients and parents was performed whe
  13. 13Implementing Whole Genome Sequencing (WGS) in Clinical Practice: Advantages, Challenges, and Future Perspectives.The integration of whole genome sequencing (WGS) into all aspects of modern medicine represents the next step in the evolution of healthcare. Using this technology, scientists and physicians can observe the entire human genome comprehensively, generating a plethora of new sequencing data. Modern computational analysis entails advanced algorithms for variant detection, as well as complex models for classification. Data science and machine learning play a crucial role in the processing and interpretation of results, using enormous databases and statistics to discover new and support current genotype-phenotype correlations. In clinical practice, this technology has greatly enabled the development of personalized medicine, approaching each patient individually and in accordance with their genetic and biochemical profile. The most propulsive areas include rare disease genomics, oncogenomics, pharmacogenomics, neonatal screening, and infectious disease genomics. Another crucial application o
  14. 14Pharmacogenomics polygenic risk score for drug response prediction using PRS-PGx methods.Polygenic risk scores (PRS) have been successfully developed for the prediction of human diseases and complex traits in the past years. For drug response prediction in randomized clinical trials, a common practice is to apply PRS built from a disease genome-wide association study (GWAS) directly to a corresponding pharmacogenomics (PGx) setting. Here, we show that such an approach relies on stringent assumptions about the prognostic and predictive effects of the selected genetic variants. We propose a shift from disease PRS to PGx PRS approaches by simultaneously modeling both the prognostic and predictive effects and further make this shift possible by developing a series of PRS-PGx methods, including a novel Bayesian regression approach (PRS-PGx-Bayes). Simulation studies show that PRS-PGx methods generally outperform the disease PRS methods and PRS-PGx-Bayes is superior to all other PRS-PGx methods. We further apply the PRS-PGx methods to PGx GWAS data from a large cardiovascular ra
  15. 15Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis.Methotrexate (MTX) is widely used and considered a first-line disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX effectiveness in RA patients, although inconsistent results have been reported. A systematic review and meta-analysis were performed to identify genetic variants associated with MTX efficacy. A total of 30 publications that included 34 genes and 125 SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the systematic review (SR), and 21 studies were included in 9 meta-analyses. Associations between MTX response in RA patients in MTHFR 1298A > C (rs1801131), ATIC 347C > G (rs2372536), RFC-1 80G > A (rs1051266), SLC19A1 A > G (rs2838956) and SLC19A1 G > A (rs7499) genetic polymorphisms were found, but not observed between the MTHFR 677C > T (rs1801133), TYMS 28 bp V
  16. 16Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers.Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher a
  17. 17Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only repla
  18. 18Genetic Variations and Cisplatin Nephrotoxicity: A Systematic Review.Background: Nephrotoxicity is a notable adverse effect in cisplatin treated patients characterized by tubular injury and/or increased serum creatinine (SCr) with incidence varying from 20 to 70%. Pharmacogenomics has been shown to identify strongly predictive genetic markers to help determine which patients are more likely to experience, for example, a serious adverse drug reaction or receive optimal benefit through enhanced efficacy. Genetic variations have been reported to influence the risk of cisplatin nephrotoxicity; however, a comprehensive overview is lacking. Methods: A systematic review was performed using Pubmed, Embase and Web of Science on clinical studies that used cisplatin-based chemotherapy as treatment, had available genotyping data, and evaluated nephrotoxicity as an outcome. The quality of reporting was assessed using the STrengthening the REporting of Genetic Association Studies (STREGA) checklist. Results: Twenty-eight eligible studies were included; all were candi
  19. 19Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review.There is wide variability in the response to inhaled corticosteroids (ICS) in asthma. While some of this heterogeneity of response is due to adherence and environmental causes, genetic variation also influences response to treatment and genetic markers may help guide treatment. Over the past years, researchers have investigated the relationship between a large number of genetic variations and response to ICS by performing pharmacogenomic studies. In this systematic review we will provide a summary of recent pharmacogenomic studies on ICS and discuss the latest insight into the potential functional role of identified genetic variants. To date, seven genome wide association studies (GWAS) examining ICS response have been published. There is little overlap between identified variants and methodologies vary largely. However, in vitro and/or in silico analyses provide additional evidence that genes discovered in these GWAS (e.g. GLCCI1 , FBXL7 , T gene , ALLC , CMTR1 ) might play a direct o
  20. 20Adopting clinical genomics: a systematic review of genomic literacy among physicians in cancer care.Background This article investigates the genomic knowledge of oncology care physicians in the adoption of clinical genomics. We apply Rogers' knowledge framework from his diffusion of innovation theory to identify three types of knowledge in the process of translation and adoption: awareness, how-to, and principles knowledge. The objectives of this systematic review are to: (1) examine the level of knowledge among physicians in clinical cancer genomics, and (2) identify potential interventions or strategies for development of genomic education for oncology practice. Methods We follow the PRIMSA statement protocol and conduct a search of five relevant electronic databases. Our review focuses on: (1) genomic knowledge of oncogenomics or genomic services in oncology practices among physicians, and (2) interventions or strategies to provide genomic education of oncogenomics for physicians. Results We include twenty-one studies in our analysis. Nine focus on interventions to provide genomic
  21. 21Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial.The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improv
  22. 22A joint NCBI and EMBL-EBI transcript set for clinical genomics and research.Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE 1 and RefSeq 2 launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequ
  23. 23Parkinson's Disease: From Pathogenesis to Pharmacogenomics.Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson's disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson's disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and
  24. 24A Review of the Important Role of <i>CYP2D6</i> in Pharmacogenomics.Cytochrome P450 2D6 ( CYP2D6 ) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics socie
  25. 25Artificial intelligence in clinical and genomic diagnostics.Artificial intelligence (AI) is the development of computer systems that are able to perform tasks that normally require human intelligence. Advances in AI software and hardware, especially deep learning algorithms and the graphics processing units (GPUs) that power their training, have led to a recent and rapidly increasing interest in medical AI applications. In clinical diagnostics, AI-based computer vision approaches are poised to revolutionize image-based diagnostics, while other AI subtypes have begun to show similar promise in various diagnostic modalities. In some areas, such as clinical genomics, a specific type of AI algorithm known as deep learning is used to process large and complex genomic datasets. In this review, we first summarize the main classes of problems that AI systems are well suited to solve and describe the clinical diagnostic tasks that benefit from these solutions. Next, we focus on emerging methods for specific tasks in clinical genomics, including variant
  26. 26Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine.The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual's particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid h
  27. 27Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer.Background The four major RNA adenosine modifications, i.e., m 6 A, m 1 A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. Methods We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subt
  28. 28Treatment-Resistant Depression Revisited: A Glimmer of Hope.Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of w
  29. 29Antifungals: From Pharmacokinetics to Clinical Practice.The use of antifungal drugs started in the 1950s with polyenes nystatin, natamycin and amphotericin B-deoxycholate (AmB). Until the present day, AmB has been considered to be a hallmark in the treatment of invasive systemic fungal infections. Nevertheless, the success and the use of AmB were associated with severe adverse effects which stimulated the development of new antifungal drugs such as azoles, pyrimidine antimetabolite, mitotic inhibitors, allylamines and echinochandins. However, all of these drugs presented one or more limitations associated with adverse reactions, administration route and more recently the development of resistance. To worsen this scenario, there has been an increase in fungal infections, especially in invasive systemic fungal infections that are particularly difficult to diagnose and treat. In 2022, the World Health Organization (WHO) published the first fungal priority pathogens list, alerting people to the increased incidence of invasive systemic fungal in
  30. 30CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations-Implication for Drug Safety, Dosing, and Individualized Therapy.Adverse drug reactions (ADRs) are one of the major causes of morbidity and mortality worldwide. It is well-known that individual genetic make-up is one of the causative factors of ADRs. Approximately 14 million single nucleotide polymorphisms (SNPs) are distributed throughout the entire human genome and every patient has a distinct genetic make-up which influences their response to drug therapy. Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of antiretroviral, antimalarial, anticancer, and antidepressant drugs. These drug classes are commonly in use worldwide and face specific population variability in side effects and dosing. Parts of this variability may be caused by single nucleotide polymorphisms (SNPs) in the CYP2B6 gene that are associated with altered protein expression and catalytic function. Population variability in the CYP2B6 gene leads to changes in drug metabolism which may result in adverse drug reactions or therapeutic failure. So far more than 30 non-synonym
  31. 31Pharmacogenomics in practice: a review and implementation guide.Considerable efforts have been exerted to implement Pharmacogenomics (PGx), the study of interindividual variations in DNA sequence related to drug response, into routine clinical practice. In this article, we first briefly describe PGx and its role in improving treatment outcomes. We then propose an approach to initiate clinical PGx in the hospital setting. One should first evaluate the available PGx evidence, review the most relevant drugs, and narrow down to the most actionable drug-gene pairs and related variant alleles. This is done based on data curated and evaluated by experts such as the pharmacogenomics knowledge implementation (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC), as well as drug regulatory authorities such as the US Food and Drug Administration (FDA) and European Medicinal Agency (EMA). The next step is to differentiate reactive point of care from preemptive testing and decide on the genotyping strategy being a candidate or panel test
  32. 32The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.Background Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mec
  33. 33Polygenic risk scores: An overview from bench to bedside for personalised medicine.Since the first polygenic risk score (PRS) in 2007, research in this area has progressed significantly. The increasing number of SNPs that have been identified by large scale GWAS analyses has fuelled the development of a myriad of PRSs for a wide variety of diseases and, more recently, to PRSs that potentially identify differential response to specific drugs. PRSs constitute a composite genomic biomarker and potential applications for PRSs in clinical practice encompass risk prediction and disease screening, early diagnosis, prognostication, and drug stratification to improve efficacy or reduce adverse drug reactions. Nevertheless, to our knowledge, no PRSs have yet been adopted into routine clinical practice. Beyond the technical considerations of PRS development, the major challenges that face PRSs include demonstrating clinical utility and circumnavigating the implementation of novel genomic technologies at scale into stretched healthcare systems. In this review, we discuss progres
  34. 34Barriers to clinical adoption of pharmacogenomic testing in psychiatry: a critical analysis.Pharmacogenomics (PGx) is the study of genetic influences on an individual's response to medications. Improvements in the quality and quantity of PGx research over the past two decades have enabled the establishment of commercial markets for PGx tests. Nevertheless, PGx testing has yet to be adopted as a routine practice in clinical care. Accordingly, policy regulating the commercialization and reimbursement of PGx testing is in its infancy. Several papers have been published on the topic of challenges, or 'barriers' to clinical adoption of this healthcare innovation. However, many do not include recent evidence from randomized controlled trials, economic utility studies, and qualitative assessments of stakeholder opinions. The present paper revisits the most cited barriers to adoption of PGx testing: evidence for clinical utility, evidence for economic effectiveness, and stakeholder awareness. We consider these barriers in the context of reviewing PGx literature published over the pas
  35. 35Rapid Genomic Diagnosis of Fungal Infections in the Age of Next-Generation Sequencing.Next-generation sequencing (NGS) technologies have recently developed beyond the research realm and started to mature into clinical applications. Here, we review the current use of NGS for laboratory diagnosis of fungal infections. Since the first reported case in 2014, >300 cases of fungal infections diagnosed by NGS were described. Pneumocystis jirovecii is the predominant fungus reported, constituting ~25% of the fungi detected. In ~12.5% of the cases, more than one fungus was detected by NGS. For P. jirovecii infections diagnosed by NGS, all 91 patients suffered from pneumonia and only 1 was HIV-positive. This is very different from the general epidemiology of P. jirovecii infections, of which HIV infection is the most important risk factor. The epidemiology of Talaromyces marneffei infection diagnosed by NGS is also different from its general epidemiology, in that only 3/11 patients were HIV-positive. The major advantage of using NGS for laboratory diagnosis is that it can pick up
  36. 36A review of real-world evidence on preemptive pharmacogenomic testing for preventing adverse drug reactions: a reality for future health care.Adverse drug reactions (ADRs) are a significant public health concern and a leading cause of hospitalization; they are estimated to be the fourth leading cause of death and increasing healthcare costs worldwide. Carrying a genetic variant could alter the efficacy and increase the risk of ADRs associated with a drug in a target population for commonly prescribed drugs. The use of pre-emptive pharmacogenetic/omic (PGx) testing can improve drug therapeutic efficacy, safety, and compliance by guiding the selection of drugs and/or dosages. In the present narrative review, we examined the current evidence of pre-emptive PGx testing-based treatment for the prevention of ADRs incidence and hospitalization or emergency department visits due to serious ADRs, thus improving patient safety. We then shared our perspective on the importance of preemptive PGx testing in clinical practice for the safe use of medicines and decreasing healthcare costs.
  37. 37Pharmacogenomics: A Genetic Approach to Drug Development and Therapy.The majority of the well-known pharmacogenomics research used in the medical sciences contributes to our understanding of medication interactions. It has a significant impact on treatment and drug development. The broad use of pharmacogenomics is required for the progress of therapy. The main focus is on how genes and an intricate gene system affect the body's reaction to medications. Novel biomarkers that help identify a patient group that is more or less likely to respond to a certain medication have been discovered as a result of recent developments in the field of clinical therapeutics. It aims to improve customized therapy by giving the appropriate drug at the right dose at the right time and making sure that the right prescriptions are issued. A combination of genetic, environmental, and patient variables that impact the pharmacokinetics and/or pharmacodynamics of medications results in interindividual variance in drug response. Drug development, illness susceptibility, and treat
  38. 38Pharmacomicrobiomics: a novel route towards personalized medicine?Inter-individual heterogeneity in drug response is a serious problem that affects the patient's wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recognized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposition (absorption, distribution, metabolism and excretion). In this review, we provide a historical overview and examine current state-of-the-art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacoge
  39. 39Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prosp
  40. 40Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components.Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle t
  41. 41Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good.The field of pharmacogenomics (PGx) is gradually shifting from the reactive testing of single genes toward the proactive testing of multiple genes to improve treatment outcomes, reduce adverse events, and decrease the burden of unnecessary costs for healthcare systems. Despite the progress in the field of pharmacogenomics, its implementation into routine care has been slow due to several barriers. However, in recent years, the number of studies on the implementation of PGx has increased, all providing a wealth of knowledge on different solutions for overcoming the obstacles that have been emphasized over the past years. This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.
  42. 42Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions.Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug-drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insuff
  43. 43A Comprehensive Review of HLA and Severe Cutaneous Adverse Drug Reactions: Implication for Clinical Pharmacogenomics and Precision Medicine.Human leukocyte antigen ( HLA ) encoded by the HLA gene is an important modulator for immune responses and drug hypersensitivity reactions as well. Genetic polymorphisms of HLA vary widely at population level and are responsible for developing severe cutaneous adverse drug reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), maculopapular exanthema (MPE). The associations of different HLA alleles with the risk of drug induced SJS/TEN, DRESS and MPE are strongly supportive for clinical considerations. Prescribing guidelines generated by different national and international working groups for translation of HLA pharmacogenetics into clinical practice are underway and functional in many countries, including Thailand. Cutting edge genomic technologies may accelerate wider adoption of HLA screening in routine clinical settings. There are great opportunities and several challenges as well fo
  44. 44Pharmacogenomics of NSAID-Induced Upper Gastrointestinal Toxicity.Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are widely used globally for the treatment of pain and inflammation, and in the case of aspirin, for secondary prevention of cardiovascular disease. Chronic non-steroidal anti-inflammatory drug use is associated with potentially serious upper gastrointestinal adverse drug reactions (ADRs) including peptic ulcer disease and gastrointestinal bleeding. A few clinical and genetic predisposing factors have been identified; however, genetic data are contradictory. Further research is needed to identify clinically relevant genetic and non-genetic markers predisposing to NSAID-induced peptic ulceration.
  45. 45Therapeutic and Toxic Effects of Valproic Acid Metabolites.Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington's disease, Parkinson's disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: β-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains th
  46. 46Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health.Both safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most
  47. 47Evaluation of race and ethnicity disparities in outcome studies of CYP2C19 genotype-guided antiplatelet therapy.Dual antiplatelet therapy with a P2Y 12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin remains the standard of care for all patients undergoing percutaneous coronary intervention (PCI). It is well-established that patients carrying CYP2C19 no function alleles have impaired capacity to convert clopidogrel into its active metabolite and thus, are at higher risk of major adverse cardiovascular events (MACE). The metabolism and clinical effectiveness of prasugrel and ticagrelor are not affected by CYP2C19 genotype, and accumulating evidence from multiple randomized and observational studies demonstrates that CYP2C19 genotype-guided antiplatelet therapy following PCI improves clinical outcomes. However, most antiplatelet pharmacogenomic outcome studies to date have lacked racial and ethnic diversity. In this review, we will (1) summarize current guideline recommendations and clinical outcome evidence related to CYP2C19 genotype-guided antiplatelet therapy, (2) evaluate the pr
  48. 48The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review.Psychotropic medication efficacy and tolerability are critical treatment issues faced by individuals with psychiatric disorders and their healthcare providers. For some people, it can take months to years of a trial-and-error process to identify a medication with the ideal efficacy and tolerability profile. Current strategies (e.g. clinical practice guidelines, treatment algorithms) for addressing this issue can be useful at the population level, but often fall short at the individual level. This is, in part, attributed to interindividual variation in genes that are involved in pharmacokinetic (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamic (e.g. receptors, signaling pathways) processes that in large part, determine whether a medication will be efficacious or tolerable. A precision prescribing strategy know as pharmacogenomics (PGx) assesses these genomic variations, and uses it to inform selection and dosing of certain psychotropic medications. In this rev
  49. 49Artificial Intelligence, Healthcare, Clinical Genomics, and Pharmacogenomics Approaches in Precision Medicine.Precision medicine has greatly aided in improving health outcomes using earlier diagnosis and better prognosis for chronic diseases. It makes use of clinical data associated with the patient as well as their multi-omics/genomic data to reach a conclusion regarding how a physician should proceed with a specific treatment. Compared to the symptom-driven approach in medicine, precision medicine considers the critical fact that all patients do not react to the same treatment or medication in the same way. When considering the intersection of traditionally distinct arenas of medicine, that is, artificial intelligence, healthcare, clinical genomics, and pharmacogenomics-what ties them together is their impact on the development of precision medicine as a field and how they each contribute to patient-specific, rather than symptom-specific patient outcomes. This study discusses the impact and integration of these different fields in the scope of precision medicine and how they can be used in p
  50. 50Applying Next-Generation Sequencing Platforms for Pharmacogenomic Testing in Clinical Practice.Pharmacogenomics (PGx) studies the use of genetic data to optimize drug therapy. Numerous clinical centers have commenced implementing pharmacogenetic tests in clinical routines. Next-generation sequencing (NGS) technologies are emerging as a more comprehensive and time- and cost-effective approach in PGx. This review presents the main considerations for applying NGS in guiding drug treatment in clinical practice. It discusses both the advantages and the challenges of implementing NGS-based tests in PGx. Moreover, the limitations of each NGS platform are revealed, and the solutions for setting up and management of these technologies in clinical practice are addressed.
  51. 51Pharmacogenomics in epilepsy.There is high variability in the response to antiepileptic treatment across people with epilepsy. Genetic factors significantly contribute to such variability. Recent advances in the genetics and neurobiology of the epilepsies are establishing the basis for a new era in the treatment of epilepsy, focused on each individual and their specific epilepsy. Variation in response to antiepileptic drug treatment may arise from genetic variation in a range of gene categories, including genes affecting drug pharmacokinetics, and drug pharmacodynamics, but also genes held to actually cause the epilepsy itself. From a purely pharmacogenetic perspective, there are few robust genetic findings with established evidence in epilepsy. Many findings are still controversial with anecdotal or less secure evidence and need further validation, e.g. variation in genes for transporter systems and antiepileptic drug targets. The increasing use of genetic sequencing and the results of large-scale collaborative p
  52. 52Machine learning and systems genomics approaches for multi-omics data.In light of recent advances in biomedical computing, big data science, and precision medicine, there is a mammoth demand for establishing algorithms in machine learning and systems genomics (MLSG), together with multi-omics data, to weigh probable phenotype-genotype relationships. Software frameworks in MLSG are extensively employed to analyze hundreds of thousands of multi-omics data by high-throughput technologies. In this study, we reviewed the MLSG software frameworks and future directions with respect to multi-omics data analysis and integration. Our review was targeted at researching recent approaches and technical solutions for the MLSG software frameworks using multi-omics platforms.
  53. 53Precision Psychiatry Applications with Pharmacogenomics: Artificial Intelligence and Machine Learning Approaches.A growing body of evidence now suggests that precision psychiatry, an interdisciplinary field of psychiatry, precision medicine, and pharmacogenomics, serves as an indispensable foundation of medical practices by offering the accurate medication with the accurate dose at the accurate time to patients with psychiatric disorders. In light of the latest advancements in artificial intelligence and machine learning techniques, numerous biomarkers and genetic loci associated with psychiatric diseases and relevant treatments are being discovered in precision psychiatry research by employing neuroimaging and multi-omics. In this review, we focus on the latest developments for precision psychiatry research using artificial intelligence and machine learning approaches, such as deep learning and neural network algorithms, together with multi-omics and neuroimaging data. Firstly, we review precision psychiatry and pharmacogenomics studies that leverage various artificial intelligence and machine l
  54. 54Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression.Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon met
  55. 55Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics.Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer type with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we find that NPC subtypes maintain distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype is characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, whereas sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibit enriched epithelial-mesenchymal transition (EMT) and invasion promoting genes, which are well correlated with their morphological features. Furthermore, patient-derived organoid (PDO)-based drug test identifies potential subtype-specific treatment regimens, in that SC and MSEC subtypes are sensitive to microtubule inhibitors, whereas EC subtype is more responsive to EGFR inhibitors, which is synergisti
  56. 56Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6 . To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psy
  57. 57Pharmacogenomic Testing: Clinical Evidence and Implementation Challenges.Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and lowering risk of serious adverse events. As of June 2019, there are 132 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels. Recently, the technology for identifying individual-specific genetic variants (genotyping) has become more accessible. Next generation sequencing (NGS) is a cost-effective option for genotyping patients at many pharmacogenomic loci simultaneously, and guidelines for implementation of these data are available from organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). NGS and related technologies are increasing knowledge in the research sphere, yet rates of genomic literacy remain low, resulting in a widening gap in knowledge translation to the patient. Multidisciplinary teams-including physicians, nurses, genetic counsellor
  58. 58Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis.Pharmacogenomic studies allowed the reasons behind the different responses to treatments to be understood. Its clinical utility, in fact, is demonstrated by the reduction in adverse drug reaction incidence and the improvement of drug efficacy. Pharmacogenomics is an important tool that is able to improve the drug therapy of different disorders. In particular, this review will highlight the current pharmacogenomics knowledge about biologics and small-molecule treatments for psoriasis. To date, studies performed on genes involved in the metabolism of biological drugs (tumor necrosis factor inhibitors and cytokines inhibitors) and small molecules (apremilast, dimethyl fumarate, and tofacitinib) have provided conflicting results, and further investigations are necessary in order to establish a set of biomarkers to be introduced into clinical practice.
  59. 59Drug-Induced Severe Cutaneous Adverse Reactions: Insights Into Clinical Presentation, Immunopathogenesis, Diagnostic Methods, Treatment, and Pharmacogenomics.SCARs are rare and life-threatening hypersensitivity reactions. In general, the increased duration of hospital stays and the associated cost burden are common issues, and in the worst-case scenario, they can result in mortality. SCARs are delayed T cell-mediated hypersensitivity reactions. Recovery can take from 2 weeks to many months after dechallenging the culprit drugs. Genetic polymorphism of the HLA genes may change the selection and presentation of antigens, allowing toxic drug metabolites to initiate immunological reactions. However, each SCARs has a different onset latency period, clinical features, or morphological pattern. This explains that, other than HLA mutations, other immuno-pathogenesis may be involved in drug-induced severe cutaneous reactions. This review will discuss the clinical morphology of various SCARs, various immune pathogenesis models, diagnostic criteria, treatments, the association of various drug-induced reactions and susceptible alleles in different popu
  60. 60p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics).SARS-CoV-2 infection affects different organs and tissues, including the upper and lower airways, the lung, the gut, the olfactory system and the eye, which may represent one of the gates to the central nervous system. Key transcriptional factors, such as p53 and NF-kB and their reciprocal balance, are altered upon SARS-CoV-2 infection, as well as other key molecules such as the virus host cell entry mediator ACE2, member of the RAS-pathway. These changes are thought to play a central role in the impaired immune response, as well as in the massive cytokine release, the so-called cytokine storm that represents a hallmark of the most severe form of SARS-CoV-2 infection. Host genetics susceptibility is an additional key side to consider in a complex disease as COVID-19 characterized by such a wide range of clinical phenotypes. In this review, we underline some molecular mechanisms by which SARS-CoV-2 modulates p53 and NF-kB expression and activity in order to maximize viral replication in
  61. 61Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.Background Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. Methods This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or signifi
  62. 62A Landscape of Pharmacogenomic Interactions in Cancer.Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to l
  63. 63Pharmacogenomics of GPCR Drug Targets.Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients' quality of life, and relieve the economic
  64. 64Metabolomics enables precision medicine: "A White Paper, Community Perspective".Introduction background to metabolomics Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry anal
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