Pharmacogenomics of Fluoropyrimidines-a Personalized Approach for Treating and Preventing Keratinocyte Carcinomas.

JAMA Dermatol. 2021 Feb 03;:

Authors: Ikediobi O

PMID: 33533896 [PubMed - as supplied by publisher]

A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival.

J Cancer. 2021;12(5):1270-1283

Authors: Wang L, Sun C, Li X, Mao C, Qian J, Wang J, Wu J, Li Q, Bai C, Han B, Gao Z, Xu J, Yin J, Liu Z, Lu D, Jin L, Wang H

Abstract
Objective: The expression and function of platinum transporters affect drug tissue concentration and therapeutic effects. We had previously characterized functional variant of platinum intake transporter SLC31A1 gene. We aimed to investigate the association of platinum efflux transporter gene ABCG2 polymorphism and combined ABCG2 and SLC31A1 polymorphisms with clinical outcomes of NSCLC patients receiving platinum-based chemotherapy. Methods: We genotyped thirteen tagging and functional SNPs of ABCG2 in 1004 patients, and assessed their association with response, toxicity and survival using unconditional logistic regression and Cox proportional hazards regression analyses respectively. Results: Nonsynonymous rs2231142 (odds ratio [OR] 2.07; 95 % confidence interval [CI] 1.26-3.63), rs1871744 (OR 0.60; 95 % CI 0.42-0.87) and their haplotype and diplotype were associated with objective response. Rs4148157 was associated with shorter overall survival (Log-rank P = 0.002; hazard ratio [HR] 1.22; 95 % CI 1.05-1.42). Furthermore, the combined SLC31A1 rs2233914 and ABCG2 rs1871744 genotype was significantly associated with poor response (OR 0.31; 95 % CI 0.17-0.56; P interaction = 0.003). And the combined genotypes of the functional rs10759637 of SLC31A1 and the nonsynonymous rs2231142 (Log-rank P = 5.20×10-5; HR 1.47; 95 % CI 1.19-1.81; P interaction = 0.007) or linked rs4148157 of ABCG2 were significantly associated with poor survival. Conclusion: This study reveals divergent association of ABCG2 polymorphism with response and survival of NSCLC patients receiving platinum-based chemotherapy, demonstrates the combined effects of functional variants of ABCG2 and SLC31A1 on clinical outcomes, and highlights pharmacogenetic relevance of platinum transporter genes interaction.

PMID: 33531973 [PubMed]

Implementation outcomes of Humanwide: integrated precision health in team-based family practice primary care.

BMC Fam Pract. 2021 Feb 02;22(1):28

Authors: Brown-Johnson CG, Safaeinili N, Baratta J, Palaniappan L, Mahoney M, Rosas LG, Winget M

Abstract
BACKGROUND: Humanwide was precision health embedded in primary care aiming to leverage high-tech and high-touch medicine to promote wellness, predict and prevent illness, and tailor treatment to individual medical and psychosocial needs.
METHODS: We conducted a study assessing implementation outcomes to inform spread and scale, using mixed methods of semi-structured interviews with diverse stakeholders and chart reviews. Humanwide included: 1) health coaching; 2) four digital health tools for blood-pressure, weight, glucose, and activity; 3) pharmacogenomic testing; and 4) genetic screening/testing. We examined implementation science constructs: reach/penetration, acceptability, feasibility, and sustainability. Chart reviews captured preliminary clinical outcomes.
RESULTS: Fifty of 69 patients (72%) invited by primary care providers participated in the Humanwide pilot. We performed chart reviews for the 50 participating patients. Participants were diverse overall (50% non-white, 66% female). Over half of the participants were obese and 58% had one or more major cardiovascular risk factor: dyslipidemia, hypertension, diabetes. Reach/penetration of Humanwide components varied: pharmacogenomics testing 94%, health coaching 80%, genetic testing 72%, and digital health 64%. Interview participants (n=27) included patients (n=16), providers (n=9), and the 2 staff who were allocated dedicated time for Humanwide patient intake and orientation. Patients and providers reported Humanwide was acceptable; it engaged patients holistically, supported faster medication titration, and strengthened patient-provider relationships. All patients benefited clinically from at least one Humanwide component. Feasibility challenges included: low provider self-efficacy for interpreting genetics and pharmacogenomics; difficulties with data integration; patient technology challenges; and additional staffing needs. Patient financial burden concerns surfaced with respect to sustainability.
CONCLUSION: This is the first report of implementation of a multi-component precision health model embedded in team-based primary care. We found acceptance from both patients and providers; however, feasibility barriers must be overcome to enable broad spread and sustainability. We found that barriers to implementation of precision health in a team-based primary care clinic are mundane and straightforward, though not necessarily easy to overcome. Future implementation endeavors should invest in basics: education, workflow, and reflection/evaluation. Strengthening fundamentals will enable healthcare systems to more nimbly accept the responsibility of meeting patients at the crossroads of innovative science and routinized clinical systems.

PMID: 33530939 [PubMed - in process]

Pharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature.

J Pers Med. 2021 Jan 26;11(2):

Authors: Ikediobi O, Schneider JA

Abstract
Severe cutaneous adverse drug reactions (SCAR) such as the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug reactions by using our knowledge of the inherited or acquired genetic risk of drug metabolizing enzymes, drug targets, or the human leukocyte antigen (HLA) genotype. Dermatologists are experts in the diagnosis and management of severe cutaneous adverse drug reactions (SCAR) in both the inpatient and outpatient setting. However, most dermatologists in the US have not focused on the prevention of SCAR. Therefore, this paper presents a case series and review of the literature highlighting salient examples of how dermatologists can apply pharmacogenomics in the diagnosis and especially in the prevention of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim, two commonly prescribed medications.

PMID: 33530463 [PubMed]

[In silico exploration of databases is no longer a fighting sport].

Bull Cancer. 2021 Jan;108(1):14-17

Authors: Robert J

PMID: 33422338 [PubMed - indexed for MEDLINE]

The Interface of Therapeutics and Genomics in Cardiovascular Medicine.

Cardiovasc Drugs Ther. 2021 Feb 02;:

Authors: Magavern EF, Kaski JC, Turner RM, Janmohamed A, Borry P, Pirmohamed M

Abstract
Pharmacogenomics has a burgeoning role in cardiovascular medicine, from warfarin dosing to antiplatelet choice, with recent developments in sequencing bringing the promise of personalised medicine ever closer to the bedside. Further scientific evidence, real-world clinical trials, and economic modelling are needed to fully realise this potential. Additionally, tools such as polygenic risk scores, and results from Mendelian randomisation analyses, are only in the early stages of clinical translation and merit further investigation. Genetically targeted rational drug design has a strong evidence base and, due to the nature of genetic data, academia, direct-to-consumer companies, healthcare systems, and industry may meet in an unprecedented manner. Data sharing navigation may prove problematic. The present manuscript addresses these issues and concludes a need for further guidance to be provided to prescribers by professional bodies to aid in the consideration of such complexities and guide translation of scientific knowledge to personalised clinical action, thereby striving to improve patient care. Additionally, technologic infrastructure equipped to handle such large complex data must be adapted to pharmacogenomics and made user friendly for prescribers and patients alike.

PMID: 33528719 [PubMed - as supplied by publisher]

Pharmacogenetic-guided cannabis usage in the community pharmacy: evaluation of a pilot program.

J Cannabis Res. 2020 Sep 01;2(1):24

Authors: Papastergiou J, Li W, Sterling C, van den Bemt B

Abstract
BACKGROUND: Pharmacists possess a skillset suited to provide evidence-based guidance to current and potential users of cannabis. Clinical pharmacogenomics research has made significant progress in defining which genetic variations are important for influencing inter-patient variability in response to cannabis. This study aims to evaluate the practicality and impact of pharmacogenetic testing in the community pharmacy to help guide in the safe use of cannabis.
METHODS: The pilot program was designed as open-label, non-randomized, and observational. Two busy, urban community pharmacies, operating under the brand Shoppers Drug Mart, in Toronto, Ontario, Canada offered pharmacogenomic testing to cannabis users as part of their professional services program over a period of 2 months. Eligible patients received buccal swabs using a DNA cheek swab kit. De-identified, barcoded samples were then sent by regular mail to an off-site CLIA-certified laboratory for analysis in Mississauga, Canada. A pharmacogenetic testing platform from Lobo Genetics® was utilized for translation of participants' DNA with respect to CYP2C9, AKT1 and COMT genetic polymorphisms. Following genomic data translation, personalized, evidence-based recommendations were generated. Pharmacists provided a cannabis pharmacogenetic consultation to patients via telephone or in-person.
RESULTS: Twenty patients enrolled in the study. Pharmacogenetic screening identified 95% as having the CYP2C9*1/*1 genotype (suggesting normal THC metabolism); 35 and 25% had AKT1 genotypes suggesting intermediate risk (C/T genotype) or high risk (C/C genotype), respectively, for cannabis-induced psychosis; and 45 and 10% had COMT genotypes suggesting intermediate risk (Val/Met genotype) or high risk (Val/Val genotype), respectively for cannabis-induced neurocognitive impairment. After the pharmacogenetic consultation, 65% of patients reported an increased comfort level in choosing a specific strength/strain of cannabis for use in the future; 75% considered the consultation of high value providing information potentially vital to their health and wellbeing.
CONCLUSION: Although the study did not find any CYP2C9 variants associated with highly diminished THC metabolism, most of these patients do carry genetic variants that may potentially predispose them to the development of psychosis and memory impairment. Similar initiatives can potentially improve patient safety and empower individuals to make informed decisions about cannabis use and possible complications.

PMID: 33526106 [PubMed]

Neuroimaging of hypothalamic mechanisms related to glucose metabolism in anorexia nervosa and obesity.

J Clin Invest. 2020 08 03;130(8):4094-4103

Authors: Simon JJ, Stopyra MA, Mönning E, Sailer S, Lavandier N, Kihm LP, Bendszus M, Preissl H, Herzog W, Friederich HC

Abstract
BACKGROUNDGiven the heightened tolerance to self-starvation in anorexia nervosa (AN), a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN.METHODSTwenty-four participants with AN, 28 normal-weight participants, and 24 healthy participants with obesity underwent 2 MRI sessions in a single-blind, randomized, case-controlled crossover study. We used an intragastric infusion of glucose and water to bypass the cephalic phase of food intake. The responsivity of the hypothalamus and the crosstalk of the hypothalamus with reward-related brain regions were investigated using high-resolution MRI.RESULTSNormal-weight control participants displayed the expected glucose-induced deactivation of hypothalamic activation, whereas patients with AN and participants with obesity showed blunted hypothalamic reactivity. Furthermore, patients with AN displayed blunted reactivity in the nucleus accumbens and amygdala. Compared with the normal-weight participants and control participants with obesity, the patients with AN failed to show functional connectivity between the hypothalamus and the reward-related brain regions during water infusion relative to glucose infusion. Finally, the patients with AN displayed typical baseline levels of peripheral appetite hormones during a negative energy balance.CONCLUSIONThese results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This study provides insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease.FUNDINGThis study was supported by a grant from the DFG (SI 2087/2-1).

PMID: 32315289 [PubMed - indexed for MEDLINE]

Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular Failure.

J Am Heart Assoc. 2021 Jan 30;:e017835

Authors: Hwang HV, Sandeep N, Nair RV, Hu DQ, Zhao M, Lan IS, Fajardo G, Matkovich SJ, Bernstein D, Reddy S

Abstract
Background In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods and Results We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 versus RV hypertrophy 334.3±30.65 versus RV failure 165.4±36.72 pmol/(s×mL), P<0.0001). Mitochondrial fission protein DRP1 (dynamin 1-like) trended toward an increase, while MFF (mitochondrial fission factor) decreased and fusion protein OPA1 (mitochondrial dynamin like GTPase) decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure. Conclusions Pressure overload-induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.

PMID: 33522250 [PubMed - as supplied by publisher]

A narrative review of current trends in liraglutide: insights into the unmet needs in management of type 2 diabetes and obesity.

J Diabetes Metab Disord. 2020 Dec;19(2):1863-1872

Authors: Hasanzad M, Sarhangi N, Nikfar S, Ostad SN, Aghaei Meybodi HR

Abstract
Liraglutide is a long-acting human glucagon-like peptide-1 (GLP-1) analogue and an effective treatment for patients with metabolic diseases including type 2 diabetes mellitus (T2DM) and obesity. This review focuses on the mechanism of action of liraglutide as a well-known glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with T2DM and obesity. The lower and the higher doses of GLP-1 RAs are used for glycaemic control in T2DM and in obesity respectively. GLP-1 RAs such as liraglutide enhance insulin secretion and inhibit glucagon release via the stimulation of glucagon-like peptide-1 receptors (GLP-1Rs). Liraglutide decreases hemoglobin A1c (HbA1c) in type 2 diabetes (T2D) patients when prescribes as monotherapy or in combination with one or more antidiabetic drugs. Usually, it is well tolerated with minor hypoglycemia in combination therapy. Liraglutide reduces cardiovascular events and related risk factors including improvement of lipid profile and control of blood pressure. Accordingly, it can be cost-effective and may be a budget neutral medication option by considering its protective effect on the cardiovascular system in long-term use in the health care plan. In the near future, by pharmacogenomics approach, prediction of the highest patient's response with the lowest adverse drug reactions and also rationality of drug development will be possible. Liraglutide can be used as a desirable medicine for glycemic control and obesity. It shows extensive evidence based benefits in diabetes complications. In this narrative review, we have summarized and evaluated studies related to the role of liraglutide in clinical practice.

PMID: 33520865 [PubMed]

The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.

Front Mol Neurosci. 2020;13:555290

Authors: Cieślik M, Gassowska-Dobrowolska M, Zawadzka A, Frontczak-Baniewicz M, Gewartowska M, Dominiak A, Czapski GA, Adamczyk A

Abstract
Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders in offspring, but the pathomechanism is largely unknown. The aim of our study was to analyse the molecular mechanisms contributing to synaptic alterations in hippocampi of adolescent rats exposed prenatally to MIA. MIA was evoked in pregnant female rats by i.p. administration of lipopolysaccharide at gestation day 9.5. Hippocampi of offspring (52-53-days-old rats) were analysed using transmission electron microscopy (TEM), qPCR and Western blotting. Moreover, mitochondrial membrane potential, activity of respiratory complexes, and changes in glutathione system were measured. It was found that MIA induced changes in hippocampi morphology, especially in the ultrastructure of synapses, including synaptic mitochondria, which were accompanied by impairment of mitochondrial electron transport chain and decreased mitochondrial membrane potential. These phenomena were in agreement with increased generation of reactive oxygen species, which was evidenced by a decreased reduced/oxidised glutathione ratio and an increased level of dichlorofluorescein (DCF) oxidation. Activation of cyclin-dependent kinase 5, and phosphorylation of glycogen synthase kinase 3β on Ser9 occurred, leading to its inhibition and, accordingly, to hypophosphorylation of microtubule associated protein tau (MAPT). Abnormal phosphorylation and dysfunction of MAPT, the manager of the neuronal cytoskeleton, harmonised with changes in synaptic proteins. In conclusion, this is the first study demonstrating widespread synaptic changes in hippocampi of adolescent offspring prenatally exposed to MIA.

PMID: 33519375 [PubMed]

Genetic Diversity of Drug-Related Genes in Native Americans of the Brazilian Amazon.

Pharmgenomics Pers Med. 2021;14:117-133

Authors: Fernandes MR, Rodrigues JCG, Maroñas O, Latorre-Pellicer A, Cruz R, Guerreiro JF, Burbano RMR, de Assumpção PP, Ribeiro-Dos-Santos A, Dos Santos SEB, Carracedo A, Dos Santos NPC

Abstract
Introduction: The genetic admixture of the Brazilian population has considerable relevance to the implementation of the principles of pharmacogenomics (PGx), as it may compromise the extrapolation of data obtained in more homogeneous world populations.
Purpose: This study aims to investigate a panel of 117 polymorphisms in 35 pharmacogenes, which contains label recommendations or clinical evidence by international drug regulatory agencies, in Amazonian Native American populations, and compare the results obtained with continental population data from the 1000 Genomes Project Consortium.
Patients and Methods: The study population is composed of 109 Native American individuals from three Brazilian Amazon groups. The genotyping of the PGx polymorphisms was performed by allelic discrimination using TaqMan® OpenArray Genotyping with a panel of 120 customized assays on the QuantStudio™ 12K Flex Real-Time PCR System.
Results: Statistical differences within the Native American populations were observed regarding both genotypes and phenotypes of some genes of the CYP family. The discriminant analysis of principal components (DAPCs) between the NAM group and the continental populations of the 1000 Genomes Project resulted in the clustering of the three Native American populations. Additionally, in general, the NAM group was determined to be closely situated between East Asia, America, and South Asia groups, which enabled us to infer a genetic similarity between these populations. The DAPC analysis further demonstrated that eight polymorphisms and six polymorphisms were more relevant in differentiating the NAM from the continental populations and the NAM populations among themselves, respectively.
Conclusion: Some investigated polymorphisms show differences among world populations, particularly with populations of European origin, for whom precision medicine protocols are primarily designed. The accumulated knowledge regarding these variations may assist in the design of specific protocols for Native American populations and populations admixed with them.

PMID: 33519226 [PubMed]

Are long-chain methotrexate polyglutamate levels the reason for LD-MTX related adverse events in inflammatory arthritis?

Expert Rev Clin Pharmacol. 2021 Feb 01;:

Authors: Sandhu A, Kaur P, Dhir V, Bhat OM

PMID: 33517814 [PubMed - as supplied by publisher]

Potential of whole-genome sequencing-based pharmacogenetic profiling.

Pharmacogenomics. 2021 Feb 01;:

Authors: Caspar SM, Schneider T, Stoll P, Meienberg J, Matyas G

Abstract
Pharmacogenetics represents a major driver of precision medicine, promising individualized drug selection and dosing. Traditionally, pharmacogenetic profiling has been performed using targeted genotyping that focuses on common/known variants. Recently, whole-genome sequencing (WGS) is emerging as a more comprehensive short-read next-generation sequencing approach, enabling both gene diagnostics and pharmacogenetic profiling, including rare/novel variants, in a single assay. Using the example of the pharmacogene CYP2D6, we demonstrate the potential of WGS-based pharmacogenetic profiling as well as emphasize the limitations of short-read next-generation sequencing. In the near future, we envision a shift toward long-read sequencing as the predominant method for gene diagnostics and pharmacogenetic profiling, providing unprecedented data quality and improving patient care.

PMID: 33517770 [PubMed - as supplied by publisher]

Research projects in human genetics in Switzerland: analysis of research protocols submitted to cantonal ethics committees in 2018.

Swiss Med Wkly. 2021 Jan 18;151:w20403

Authors: Driessen S, Gervasoni P

Abstract
AIM OF THE STUDY: This analysis provides a full national overview of genetic research dossiers pertaining to clinical and nonclinical trials, and to further-use research projects submitted for approval to ethics committees in Switzerland in 2018. It addresses the research type, medical field, number of individuals or datasets involved, diagnostic laboratories and data privacy, as well as the procedures foreseen for obtaining consent, communicating results, and dealing with excess data and incidental findings. The analysis results should constitute a basis for future discussions surrounding regulatory and ethical procedures that govern genetic investigations in biomedical research in Switzerland.
METHODS: All research dossiers approved by ethics committees in 2018 were screened for genetic investigations. A sample of 122 dossiers were analysed in depth, with regards to the frequency of genetic investigations, overall purpose and number of human beings or datasets included, in addition to the diagnostic categories and methodologies that were employed. The number of genes, biosample storage conditions and laboratory types concerned were also recorded. The processes for obtaining informed consent, communicating the results to the participants and predetermined principles for handling incidental findings were analysed.
RESULTS: Genetic investigations were retrieved from 9% of all research applications. The focus of most clinical trials was pharmacogenetics, whereas research projects of further use of data and/or biological material were mostly investigator-initiated and focused on basic genetic research and multiple gene analysis. Overall, big datasets (i.e., more than 100 or even 1000 sets) were included, especially in further-use research projects. Nongermline somatic genetic investigations were a large research field in oncology (56%), whereas genetic germline testing was mostly performed in neurology or psychiatry. In most cases, numerous genes were analysed. Modern sequencing techniques were employed, rendering excess genetic information nearly inevitable. Information regarding the storage of genetic data was mostly lacking, whereas information regarding the biosample storage was mostly provided. Data protection and informed consent procedures aligned with legal, regulatory and ethical standards. Procedures for communicating genetic analysis results and incidental findings to research participants were not predetermined in most research protocols, and they were handled differently from informed consent and general consent forms.
CONCLUSIONS: This study overviewed the key dimensions of regulatory and ethical assessments pertaining to genetic investigations that are performed on human beings as part of research projects in Switzerland. The data&rsquo;s potential impact to shape the Federal Act on Human Genetic Testing and the Human Research Act in the future is also discussed. A direct transfer of standards for quality, consultation and communication of genetic testing within clinical genetic routines to genetic testing of human beings in the research context is neither required nor appropriate. It would bear a high risk of excluding patients and the Swiss health system from seminal innovations in medicine and life-science research.

PMID: 33516165 [PubMed - as supplied by publisher]

HIF1A polymorphisms do not modify the risk of epilepsy nor cerebral palsy after neonatal hypoxic-ischemic encephalopathy.

Brain Res. 2021 Jan 27;:147281

Authors: Kukec E, Goričar K, Dolžan V, Rener Primec Z

Abstract
PURPOSE: Hypoxic-ischemic encephalopathy (HIE) remains the major cause of cerebral palsy and epilepsy in developed countries. Hypoxia-inducible factor 1 alpha (HIF-1α) is the key mediator of oxygen homoeostasis. The aim of this study was to investigate whether hypoxia-inducible factor 1 subunit alpha (HIF1A) functional polymorphisms are associated with the risk of epilepsy, drug-resistant epilepsy, and cerebral palsy after neonatal HIE.
METHODS: The study included 139 healthy controls and 229 patients with epilepsy and/or cerebral palsy, of which 95 had perinatal HIE. Genomic DNA isolated from buccal swabs or peripheral blood were genotyped for HIF1A rs11549465 and rs11549467 using PCR based methods.
RESULTS: The investigated HIF1A polymorphisms did not influence the risk of epilepsy and its drug-resistance nor cerebral palsy after neonatal HIE (all p > 0.05). Clinical characteristics of patients were significantly associated with neurological deficits after HIE.
CONCLUSION: This study found no statistically significant association of HIF1A rs11549465 and rs11549467 with the development of epilepsy and its drug-resistance, as well as cerebral palsy, after neonatal HIE.

PMID: 33515534 [PubMed - as supplied by publisher]

Pharmacogenetics of tamoxifen therapy in Asian populations: from genetic polymorphism to clinical outcomes.

Eur J Clin Pharmacol. 2021 Jan 29;:

Authors: Wang T, Zhou Y, Cao G

Abstract
BACKGROUND: Compared with western countries, Asian breast cancer patients have unique pathological and biological characteristics. Most of them are premenopausal women with HR positive. Tamoxifen as the first-line drug for premenopausal women with HR+ is involved in multiple enzymes and transporters during metabolizing and transporting process. Variants that cause decreased or inactive gene products leading to abnormal responses in tamoxifen therapy have well been studied in western countries, whereas such information is much less reported in Asian populations.
OBJECTIVE: In order to elucidate the relationship between genetic variants and tamoxifen-induced individual drug reactions in different Asian populations and further identify genotypes/phenotypes with potential therapeutic significance.
METHODS: We reviewed the frequencies of genetic variants in major enzymes and transporter genes involved in the metabolism and transport of tamoxifen across Asian populations as well as significant correlations between genotypes/metabolic phenotypes and metabolites concentrations or BC clinical outcomes.
RESULTS: Significant inter-ethnic differences in allele frequencies was found among Asian populations, such as CYP2D6*4, *10, *41, CYP2C9*2, ABCB1 C3435T and SLCO1B1*5, and CYP2D6*10/*10 is the most common genotype correlated with adverse clinical outcomes. Moreover, we summarized the barriers and controversies of implementing pharmacogenetics in tamoxifen therapy and concluded that more population-specific pharmacogenetic studies are needed in the future.
CONCLUSION: This review revealed more systematic pharmacogenomics of genes involved in the metabolism and transport besides CYP2D6, are required to optimize the genotyping strategies and guide the personalized tamoxifen therapy in Asian populations.

PMID: 33515076 [PubMed - as supplied by publisher]

Selective Serotonin Reuptake Inhibitor Pharmaco-Omics: Mechanisms and Prediction.

Front Pharmacol. 2020;11:614048

Authors: Nguyen TTL, Liu D, Ho MF, Athreya AP, Weinshilboum R

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are a standard of care for the pharmacotherapy of patients suffering from Major Depressive Disorder (MDD). However, only one-half to two-thirds of MDD patients respond to SSRI therapy. Recently, a "multiple omics" research strategy was applied to identify genetic differences between patients who did and did not respond to SSRI therapy. As a first step, plasma metabolites were assayed using samples from the 803 patients in the PGRN-AMPS SSRI MDD trial. The metabolomics data were then used to "inform" genomics by performing a genome-wide association study (GWAS) for plasma concentrations of the metabolite most highly associated with clinical response, serotonin (5-HT). Two genome-wide or near genome-wide significant single nucleotide polymorphism (SNP) signals were identified, one that mapped near the TSPAN5 gene and another across the ERICH3 gene, both genes that are highly expressed in the brain. Knocking down TSPAN5 and ERICH3 resulted in decreased 5-HT concentrations in neuroblastoma cell culture media and decreased expression of enzymes involved in 5-HT biosynthesis and metabolism. Functional genomic studies demonstrated that ERICH3 was involved in clathrin-mediated vesicle formation and TSPAN5 was an ethanol-responsive gene that may be a marker for response to acamprosate pharmacotherapy of alcohol use disorder (AUD), a neuropsychiatric disorder highly co-morbid with MDD. In parallel studies, kynurenine was the plasma metabolite most highly associated with MDD symptom severity and application of a metabolomics-informed pharmacogenomics approach identified DEFB1 and AHR as genes associated with variation in plasma kynurenine levels. Both genes also contributed to kynurenine-related inflammatory pathways. Finally, a multiply replicated predictive algorithm for SSRI clinical response with a balanced predictive accuracy of 76% (compared with 56% for clinical data alone) was developed by including the SNPs in TSPAN5, ERICH3, DEFB1 and AHR. In summary, application of a multiple omics research strategy that used metabolomics to inform genomics, followed by functional genomic studies, identified novel genes that influenced monoamine biology and made it possible to develop a predictive algorithm for SSRI clinical outcomes in MDD. A similar pharmaco-omic research strategy might be broadly applicable for the study of other neuropsychiatric diseases and their drug therapy.

PMID: 33510640 [PubMed]

Healthcare Professionals' Knowledge of Pharmacogenetics and Attitudes Towards Antimicrobial Utilization in Zambia: Implications for a Precision Medicine Approach to Reducing Antimicrobial Resistance.

Front Pharmacol. 2020;11:551522

Authors: Mufwambi W, Stingl J, Masimirembwa C, Manasa J, Nhachi C, Stadler N, Mwila C, Kalungia AC, Mukosha M, Mutiti CS, Kamoto A, Kaonga P, Godman B, Munkombwe D

Abstract
Introduction: Sub-Saharan Africa and other low- and middle-income countries (LMICs) have the highest rates of antimicrobial resistance (AMR) driven by high rates of antimicrobial utilization. This is a concern as AMR appreciably increases morbidity, mortality and costs. Pharmacogenetics (PGx) and precision medicine are emerging approaches to combat AMR. Consequently, as a first step there is a need to assess AMR knowledge and attitudes, and knowledge of PGx, among healthcare professionals and use the findings to guide future interventions. Methodology: We conducted a cross-sectional study involving 304 healthcare professionals at tertiary hospitals in Lusaka, Zambia. Structural Equation Modeling (SEM) was used to analyze relationships among latent variables. Results: Overall correctness of answers concerning AMR among healthcare professionals was 60.4% (7/11). Knowledge of pharmacogenetics was low (38%). SEM showed that high AMR knowledge score correlated with a positive attitude toward combating AMR (p < 0.001). Pharmacists had relatively higher AMR knowledge scores (mean = 7.67, SD = 1.1), whereas nurses had lower scores (mean = 5.57, SD = 1.9). A minority of respondents [31.5% (n = 95)] indicated that poor access to local antibiogram data promoted AMR, with the majority [56.5% (n = 190)] responding that poor adherence to prescribed antimicrobials can lead to AMR. Pharmacists had the highest scores for attitude (mean = 5.60, SD = 1.6) whereas nurses had the lowest scores (mean = 4.02, SD = 1.4). Conclusion: AMR knowledge and attitudes, as well as knowledge on PGx among healthcare professionals in Zambia, is sub-optimal and has the potential to affect the uptake of precision medicine approaches to reduce AMR rates. Educational and positive behavioral change interventions are required to address this and in future, we will be seeking to introduce these to improve the use of antimicrobials.

PMID: 33510634 [PubMed]

Subanalysis of the CYP-GUIDES Trial: CYP2D6 Functional Stratification and Operational Timeline Selection.

Psychiatry Res. 2020 Nov 15;297:113571

Authors: Ruaño G, Tortora J, Robinson S, Baker S, Holford T, Winokur A, Goethe JW

Abstract
CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients. CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients. We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

PMID: 33513485 [PubMed - as supplied by publisher]