Precision medicine and therapies of the future.

Epilepsia. 2020 Jul 24;:

Authors: Sisodiya SM

Abstract
Precision medicine in the epilepsies has gathered much attention, especially with gene discovery pushing forward new understanding of disease biology. Several targeted treatments are emerging, some with considerable sophistication and individual-level tailoring. There have been rare achievements in improving short-term outcomes in a few very select patients with epilepsy. The prospects for further targeted, repurposed, or novel treatments seem promising. Along with much-needed success, difficulties are also arising. Precision treatments do not always work, and sometimes are inaccessible or do not yet exist. Failures of precision medicine may not find their way to broader scrutiny. Precision medicine is not a new concept: It has been boosted by genetics and is often focused on genetically determined epilepsies, typically considered to be driven in an individual by a single genetic variant. Often the mechanisms generating the full clinical phenotype from such a perceived single cause are incompletely understood. The impact of additional genetic variation and other factors that might influence the clinical presentation represent complexities that are not usually considered. Precision success and precision failure are usually equally incompletely explained. There is a need for more comprehensive evaluation and a more rigorous framework, bringing together information that is both necessary and sufficient to explain clinical presentation and clinical responses to precision treatment in a precision approach that considers the full picture not only of the effects of a single variant, but also of its genomic and other measurable environment, within the context of the whole person. As we may be on the brink of a treatment revolution, progress must be considered and reasoned: One possible framework is proposed for the evaluation of precision treatments.

PMID: 32776321 [PubMed - as supplied by publisher]

Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

J Can Acad Child Adolesc Psychiatry. 2020 Aug;29(3):188-201

Authors: Sengupta SM, Grizenko N, Fortier MÈ, Ter-Stepanian M, Joober R

Abstract
Objective: The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder.
Method: We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions.
Results: Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder.
Conclusion: These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder.

PMID: 32774401 [PubMed - as supplied by publisher]

Knowledge, Attitude, Future Expectations, and Perceived Barriers of Medical Students and Physicians Regarding Pharmacogenomics in Jordan.

Int J Clin Pract. 2020 Aug 09;:e13658

Authors: Alzoubi A, Kanaan H, Alhazaimeh D, Gharaibeh S, Mukattash T, Kheirallah K

Abstract
BACKGROUND: Pharmacogenomics (PG) is a modern tool of personalizing treatment protocols to improve the efficacy and safety of drug prescriptions. These benefits are offset by a slow uptake in clinical application due to a host of physician factors, patient factors, and/or health system factors. Our study, thus, aimed to determine the knowledge, attitude, future expectations, and perceived barriers of medical students and physicians in Jordan regarding PG testing.
METHODS: A descriptive, cross-sectional study was conducted between February-August 2019. Physicians and senior medical students from academic and non-academic institutions in North Jordan (n=424) were surveyed. A structured, self-administered questionnaire was designed and piloted for the purpose of the study. A scoring system for each dimension assessed was calculated and presented using means. Mean scores were compared by sociodemographic and professional variables.
RESULTS: The response rate was 70.7%. The mean total PG knowledge score (±SD) was 5.42 (±1.51) out of 10, with a significantly higher mean among respondents aged <30 years (5.54 ± 1.43) compared to those ≥30 years-old (5.21 ± 1.62; p= 0.03). The mean total PG attitude score was 21.18 (±2.58) out of 24, with significant differences by seniority levels evident (p= 0.03). The future expectations of PG among our sample were high, with a mean score of 10.44 (±1.64) out of 12. The top three perceived barriers in applying PG were the high cost, lack of clinical guidelines, and limited knowledge and awareness.
CONCLUSION: Physicians and medical students in Jordan have low overall knowledge, albeit strongly positive attitude and future expectations toward PG, despite the perceived high cost and lack of clinical guidelines. Thus, we strongly recommend adopting a comprehensive educational strategy that aims to integrate PG concepts into medical curricula, and promote the culture of continuous medical education about PG among practitioners.

PMID: 32772487 [PubMed - as supplied by publisher]

Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial.

Alcohol Clin Exp Res. 2020 Aug 09;:

Authors: Anton RF, Voronin KE, Book SW, Latham PK, Randall PK, Glen WB, Hoffman M, Schacht JP

Abstract
BACKGROUND: While the opiate antagonist, naltrexone, is approved for Alcohol Use Disorder (AUD), not everyone benefits. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-o-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response.
METHODS: Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/day) or placebo based on their OPRM1 genotype (75 G allele carriers and 77 A allele homozygotes) and also genotyped for DAT1 VNTR (9 vs 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes.
RESULTS: Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p=0.021, d=0.72) or COMT val/val genotypes (p=0.05, d=0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p=0.09, d=0.70) or COMT met carriers (p=0.03, d=0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers.
CONCLUSIONS: These results suggest that Individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.

PMID: 32772383 [PubMed - as supplied by publisher]

Genome-wide transcriptomics identifies an early preclinical signature of prion infection.

PLoS Pathog. 2020 06;16(6):e1008653

Authors: Sorce S, Nuvolone M, Russo G, Chincisan A, Heinzer D, Avar M, Pfammatter M, Schwarz P, Delic M, Müller M, Hornemann S, Sanoudou D, Scheckel C, Aguzzi A

Abstract
The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance and splicing alterations during the course of disease in prion-inoculated mice. Prion infection induced PrP-dependent transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical signs, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, could be the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed signs in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.

PMID: 32598380 [PubMed - indexed for MEDLINE]

In vitro sulfonation of 7-hydroxycoumarin derivatives in liver cytosol of human and six animal species.

Xenobiotica. 2020 Aug;50(8):885-893

Authors: Juvonen RO, Pentikäinen O, Huuskonen J, Timonen J, Kärkkäinen O, Heikkinen A, Fashe M, Raunio H

Abstract
Sulfonation is an important high affinity elimination pathway for phenolic compounds.In this study sulfonation of 7-hydroxycoumarin and 13 its derivatives were evaluated in liver cytosols of human and six animal species. 7-hydroxycoumarin and its derivatives are strongly fluorescent, and their sulfate conjugates are nonfluorescent at excitation 405 nm and emission 460 nm. A convenient fluorescence based kinetic assay of sulfonation was established.The sulfonation rate of most of the 7-hydroxycoumarin derivatives was low in liver cytosol of human and pig, whereas it was high with most compounds in dog and intermediate in rat, mouse, rabbit, and sheep. Sulfonation of the 7-hydroxycoumarin derivatives followed Michaelis-Menten kinetics with Km values of 0.1-12 µM, Vmax of 0.005-1.7 µmol/(min * g protein) and intrinsic clearance (Vmax/Km) of 0.004-1.9 L/(min * g cytosolic protein).Fluorescence based measurement of sulfonation of 7-hydroxycoumarin derivatives provides a sensitive and convenient high-throughput assay to determine sulfonation rate in different species and tissues and can be applied to evaluate sulfonation kinetics and inhibition.

PMID: 31903849 [PubMed - indexed for MEDLINE]

The epigenetics changes associated with anthracyclines induced cardiotoxicity.

Clin Transl Sci. 2020 Aug 08;:

Authors: Tantawy M, Pamittan FG, Singh S, Gong Y

Abstract
Advances in cancer treatment have significantly improved the survival of cancer patients, but unfortunately, many of these treatments also have long-term complications. Cancer treatmement related cardiotoxicities is becoming a significant clinical problem that a new discipline, Cardio-Oncology, was established to advance the cardiovascular care of growing cancer patient populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline-induced cardiotoxicity (AIC), which can lead to heart failure (HF). Early-onset cardiotoxicity appears within a year of treatment, while late-onset cardiotoxicity occurs more than one year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species (ROS) that lead to lipid peroxidation, defective mitochrondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This article will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.

PMID: 32770710 [PubMed - as supplied by publisher]

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing.

Clin Pharmacol Ther. 2020 Aug 08;:

Authors: Lima JJ, Thomas CD, Barbarino J, Desta Z, Van Driest SL, El Rouby N, Johnson JA, Cavallari LH, Shakhnovich V, Thacker DL, Scott SA, Schwab M, Uppugunduri CRS, Formea CM, Franciosi JP, Sangkuhl K, Gaedigk A, Klein TE, Gammal RS, Furuta T

Abstract
Proton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by CYP2C19 into inactive metabolites, and CYP2C19 genotype has been linked to PPI exposure, efficacy, and adverse effects. We summarize the evidence from the literature and provide therapeutic recommendations for PPI prescribing based on CYP2C19 genotype (updates at www.cpicpgx.org). The potential benefits of using CYP2C19 genotype data to guide PPI therapy include 1) identifying patients with genotypes predictive of lower plasma exposure and prescribing them a higher dose that will increase the likelihood of efficacy; and 2) identifying patients on chronic therapy with genotypes predictive of higher plasma exposure and prescribing them a decreased dose to minimize the risk of toxicity that is associated with long-term PPI use, particularly at higher plasma concentrations.

PMID: 32770672 [PubMed - as supplied by publisher]

The "Virtual Digital Twins" Concept in Precision Nutrition.

Adv Nutr. 2020 Aug 08;:

Authors: Gkouskou K, Vlastos I, Karkalousos P, Chaniotis D, Sanoudou D, Eliopoulos AG

Abstract
Nutritional and lifestyle changes remain at the core of healthy aging and disease prevention. Accumulating evidence underscores the impact of genetic, metabolic, and host gut microbial factors on individual responses to nutrients, paving the way for the stratification of nutritional guidelines. However, technological advances that incorporate biological, nutritional, lifestyle, and health data at an unprecedented scale and depth conceptualize a future where preventative dietary interventions will exceed stratification and will be highly individualized. We herein discuss how genetic information combined with longitudinal metabolomic, immune, behavioral, and gut microbial parameters, and bioclinical variables could define a digital replica of oneself, a "virtual digital twin," which could serve to guide nutrition in a personalized manner. Such a model may revolutionize the management of obesity and its comorbidities, and provide a pillar for healthy aging.

PMID: 32770212 [PubMed - as supplied by publisher]

Paracetamol vs. Ibuprofen in Preterm Infants With Hemodynamically Significant Patent Ductus Arteriosus: A Non-inferiority Randomized Clinical Trial Protocol.

Front Pediatr. 2020;8:372

Authors: García-Robles A, Gimeno Navarro A, Serrano Martín MDM, Párraga Quiles MJ, Parra Llorca A, Poveda-Andrés JL, Vento Torres M, Aguar Carrascosa M

Abstract
Background: Currently, the first line treatment of persistent ductus arteriosus (PDA) is either indomethacin or ibuprofen. However, the potentially life-threatening side effects associated to their use have prompted physicians to look for alternative options. The incorporation of paracetamol as an alternative to ibuprofen in the management of PDA is still based on insufficient clinical evidence. Hence, more clinical trials are needed to establish a therapeutic role for paracetamol in the management of PDA that take into consideration short- and long-term safety and efficacy outcomes. Study Design: This is a non-inferiority, randomized, multicenter, double-blinded study to evaluate the efficacy, and safety of intravenous (IV) paracetamol vs. IV ibuprofen (standard treatment) for PDA in preterm patients with a gestational age ≤ 30 weeks. At baseline, patients will be randomized (1:1) to treatment with paracetamol or ibuprofen. The primary endpoint is closure of the ductus after the first treatment course. Secondary endpoints are related to effectiveness (need for a second treatment course, rescue treatment, reopening rate, time to definitive closure, need for surgical ligation), safety (early and long-term complications), pharmacokinetics, and pharmacodynamics, pharmacogenetics, pharmacoeconomics, and genotoxicity. Long-term follow-up to 24 months of corrected postnatal age will be performed using Bayley III neurodevelopmental scale. Trial Registration: ClinicalTrials.gov Identifier: NCT04037514. EudraCT: 2015-003177-14.

PMID: 32766181 [PubMed - as supplied by publisher]

Corrigendum: Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

Front Pharmacol. 2020;11:1072

Authors: Mallah N, Zapata-Cachafeiro M, Aguirre C, Ibarra-García E, Palacios-Zabalza I, Macías-García F, Domínguez-Muñoz JE, Piñeiro-Lamas M, Ibáñez L, Vidal X, Vendrell L, Martin-Arias L, Sáinz-Gil M, Velasco-González V, Figueiras A

Abstract
[This corrects the article DOI: 10.3389/fphar.2020.00860.].

PMID: 32765275 [PubMed - as supplied by publisher]

Development of Customizable Implementation Guides to Support Clinical Adoption of Pharmacogenomics: Experiences of the Implementing GeNomics In pracTicE (IGNITE) Network.

Pharmgenomics Pers Med. 2020;13:217-226

Authors: Duong BQ, Arwood MJ, Hicks JK, Beitelshees AL, Franchi F, Houder JT, Limdi NA, Cook KJ, Owusu Obeng A, Petry N, Tuteja S, Elsey AR, Cavallari LH, Wiisanen K, IGNITE Network

Abstract
Introduction: Clinical adoption of genomic medicine has lagged behind the pace of scientific discovery. Practice-based resources can help overcome implementation challenges.
Methods: In 2015, the IGNITE (Implementing GeNomics In pracTicE) Network created an online genomic medicine implementation resource toolbox that was expanded in 2017 to incorporate the ability for users to create targeted implementation guides. This expansion was led by a multidisciplinary team that developed an evidence-based, structured framework for the guides, oversaw the technical process/build, and pilot tested the first guide, CYP2C19-Clopidogrel Testing Implementation.
Results: Sixty-five resources were collected from 12 institutions and categorized according to a seven-step implementation framework for the pilot CYP2C19-Clopidogrel Testing Implementation Guide. Five months after its launch, 96 CYP2C19-Clopidogrel Testing Implementation Guides had been created. Eighty percent of the resources most frequently selected by users were created by IGNITE to fill an identified resource gap. Resources most often included in guides were from the test reimbursement (22%), Implementation support gathering (22%), EHR integration (17%), and genetic testing workflow steps (17%).
Conclusion: Lessons learned from this implementation guide development process provide insight for prioritizing development of future resources and support the value of collaborative efforts to create resources for genomic medicine implementation.

PMID: 32765043 [PubMed - as supplied by publisher]

Analysis of Comprehensive Pharmacogenomic Profiling of VIP Variants Among the Genetically Isolated Chechen Subpopulation from Jordan.

Pharmgenomics Pers Med. 2020;13:199-215

Authors: Al-Eitan LN, Rababa'h DM, Hakooz NM, Alghamdi MA, Dajani RB

Abstract
Background: Profiling rare variants in isolated populations can significantly clarify and understand the development of a clinically relevant process. Therefore, leading to a better identifying novel targeted treatment.
Objective: This study aimed to determine the allele frequencies of 56 single nucleotide polymorphisms (SNPs) within several important pharmacogenes.
Methods: This study consisted of 166 unrelated subjects from a genetically isolated group (Chechen) who were living in Jordan. In this study, the distribution of the variants among Chechen was compared to other ethnic groups available at two databases (Genome 1000 and (ExAC)). The frequency of genotypes and alleles was calculated and tested using the chi-square test and the Hardy-Weinberg equilibrium equation (HWE).
Results: Our results revealed that the distribution of allele frequencies within different pharmacogenes among Chechen showed different similarities with other populations. The CEU and TSI showed the highest resemblance with the Chechen population (75% similarity), in contrast to LWK which had the lowest similarity (30%).
Conclusion: This study sheds light on clinically relevant SNPs to enhance medical research and apply pharmacogenomics in clinical settings.

PMID: 32765042 [PubMed - as supplied by publisher]

Discovery of new benzhydrol biscarbonate esters as potent and selective apoptosis inducers of human melanomas bearing the activated ERK pathway: SAR studies on an ERK MAPK signaling modulator, ACA-28.

Bioorg Chem. 2020 Jul 25;103:104137

Authors: Satoh R, Hamada N, Yamada A, Kanda Y, Ishikawa F, Takasaki T, Tanabe G, Sugiura R

Abstract
The recent discovery that an ERK signaling modulator [ACA-28 (2a)] preferentially kills human melanoma cell lines by inducing ERK-dependent apoptosis has generated significant interest in the field of anti-cancer therapy. In the first SAR study on 2a, here, we successfully developed candidates (2b, 2c) both of which induce more potent and selective apoptosis towards ERK-active melanoma cells than 2a, thus revealing the structural basis for inducing the ERK-dependent apoptosis and proposing the therapeutic prospect of these candidates against ERK-dependent cancers represented by melanoma.

PMID: 32763519 [PubMed - as supplied by publisher]

Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations.

Eur J Pharmacol. 2020 Aug 04;:173454

Authors: Paniri A, Hosseini MM, Rasoulinejad A, Akhavan-Niaki H

Abstract
Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.

PMID: 32763298 [PubMed - as supplied by publisher]

The eye: "An organ that must not be forgotten in coronavirus disease 2019 (COVID-2019) pandemic".

J Optom. 2020 Jul 15;:

Authors: Durán C SC, Mayorga G DC

Abstract
The coronavirus family is a group of zoonotic viruses with some recognized reservoirs particularly some bats. A novel coronavirus emerged in the province of Wuhan (China) in December of 2019.The number of infected patient with serious respiratory infection quickly spread around the world to become a global pandemic. The clinical presentation and viral pathogenesis of the coronavirus disease named COVID-19 indicated that the virus is transmitted from person to person through infected droplets entering the respiratory mucosa. Close contact with infected individuals particularly in crowded environments has characterized the rapid spread of the infection. Clinical manifestations of the viral infection have mentioned the presence of some ocular findings such as conjunctival congestion, conjunctivitis and even corneal injury associated with the classical COVID-19 infection. Some animal models of different coronaviruses eye infections have described the viral pathogenesis through tear and conjunctival sampling. On the other hand, we are recommended protective measure to prevent contagion and limit the spread of the virus in health care professionals and contact lenses wearers.

PMID: 32763128 [PubMed - as supplied by publisher]

Hmong participants' reactions to return of individual and community pharmacogenetic research results: "A positive light for our community".

J Community Genet. 2020 Aug 06;:

Authors: Holzer K, Culhane-Pera KA, Straka RJ, Wen YF, Lo M, Lee K, Xiong T, Peng K, Bishop J, Thyagarajan B, Zierhut HA

Abstract
Pharmacogenetic research has historically lacked racial and ethnic diversity, limiting the application of findings to minority populations. Recent studies, including the Hmong, have gauged communities' interest in participating in genomic research and receiving their individual results. This study was conducted to create a culturally and linguistically appropriate format to return pharmacogenomic results and identify Minnesota Hmong research participants' reactions to their personal and collective results. Using a community-based participatory research approach, researchers collaborated with Hmong community members to format the pharmacogenetic disclosure process. Three focus groups were completed with 24 Hmong participants and three major themes emerged using thematic analysis. Many Hmong focus group participants viewed the results positively, finding them useful for themselves and their community as a means to optimize responses to and avoid harms from medicines. However, some participants expressed concerns about harms that the pharmacogenetic information could bring, including anxiety, misunderstanding, discrimination, exploitation, and lack of a clinician involvement in interpreting and applying the result. Many participants interpreted their results through an experiential lens, trusting their experience of medicines more than trusting genetic information, and through a cultural lens, expressing the belief that environmental factors may influence how people's bodies respond to medicines by influencing their inherited flesh and blood (roj ntsha). Lastly, participants stressed the importance of disseminating the information while acknowledging the complex linguistic, educational, and cultural factors that limit understanding of the results. Researchers, genetic counselors, pharmacists, and healthcare providers should strive to return results in meaningful ways to all members of society.

PMID: 32761465 [PubMed - as supplied by publisher]

Human CYP2D6 in the Brain Is Protective Against Harmine-Induced Neurotoxicity: Evidence from Humanized CYP2D6 Transgenic Mice.

Mol Neurobiol. 2020 Aug 06;:

Authors: Stocco MR, Tolledo C, Wadji FB, Gonzalez FJ, Miksys S, Tyndale RF

Abstract
CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.

PMID: 32761352 [PubMed - as supplied by publisher]

Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population.

J Hum Genet. 2020 Aug 05;:

Authors: Fukunaga K, Hishinuma E, Hiratsuka M, Kato K, Okusaka T, Saito T, Ikeda M, Yoshida T, Zembutsu H, Iwata N, Mushiroda T

Abstract
Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the Vmax/Km value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.

PMID: 32759992 [PubMed - as supplied by publisher]

Pharmacogenomics, Pharmacokinetics and Circulating Proteins as Biomarkers for Bevacizumab Treatment Optimization in Patients with Cancer: A Review.

J Pers Med. 2020 Aug 04;10(3):

Authors: Papachristos A, Sivolapenko GB

Abstract
Bevacizumab is a monoclonal antibody that targets VEGF-A and inhibits tumor angiogenesis. Bevacizumab is approved for the treatment of various cancer, including metastatic colorectal cancer (mCRC), ovarian cancer, lung cancer, and others. Thus, it is widely used in oncology, but contrary to other therapeutic classes, there is still a lack of validating predictive factors for treatment outcomes with these agents. In recent years, the research for factors predictive of anti-VEGF treatments and especially bevacizumab response has been one of the most competitive translational research fields. Herein, we review and present the available literature of the clinical use of biomarkers, pharmacogenomics (PG), and therapeutic drug monitoring (TDM) approaches that can be used for the optimization of bevacizumab use in the era of precision medicine.

PMID: 32759686 [PubMed]