Gene expression network analysis provides potential targets against SARS-CoV-2.

Sci Rep. 2020 Dec 14;10(1):21863

Authors: Hernández Cordero AI, Li X, Yang CX, Milne S, Bossé Y, Joubert P, Timens W, van den Berge M, Nickle D, Hao K, Sin DD

Abstract
Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR < 0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 31 of these genes were enriched in the gene ontology biologic process 'receptor-mediated endocytosis', and 52 TMPRSS2-correlated genes had known interactions with drug compounds. Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may accelerate the development of COVID-19 therapeutics.

PMID: 33318519 [PubMed - in process]

Determination of fluoroquinolones in dried plasma spots by using microwave-assisted extraction coupled to ultra-high performance liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring.

J Pharm Biomed Anal. 2020 Dec 02;:113821

Authors: Brahmadhi A, Chen MX, Wang SY, Cho YY, Yu MC, Lee CH, Tsai IL

Abstract
Therapeutic drug monitoring is important for achieving desirable outcomes in tuberculosis treatment. In this study, microwave-assisted extraction was used to extract levofloxacin, ciprofloxacin, and moxifloxacin from dried plasma spots for subsequent detection and quantification with ultra-high performance liquid chromatography-tandem mass spectrometry. Dried plasma spotting was performed by dropping 15 μL of plasma on a protein saver card. Analyte extraction was performed with microwave-assisted extraction at 400 W for 40 s in 90 % methanol. Samples were analyzed with a core-shell C18 column (100 mm × 2.1 mm, 2.6 μm, 100 Å). Multiple reaction monitoring was used and the ion source was operated in positive electrospray ionization mode. The correlation coefficients of the calibration curves were > 0.999 for all three drugs over a range of 0.2-20 μg/mL. The intraday precision (n = 5) of the peak area ratios of the analyte to the internal standard was between 1.3 and 4.0 % relative standard deviation (RSD). The intraday accuracy ranged from 93.6-106.9%. The interday (n = 3) precision of the peak area ratios ranged from 1.9 to 8.8 % RSD, and the accuracy ranged from 94.9-107.1%. Regarding clinical application, the quantification results for moxifloxacin from dried plasma spots (DPSs) were strongly similar to the results from the plasma samples, which showed that Pearson's rho > 0.949. The validation and application results showed that the developed method can be used as an efficient analytical technique for therapeutic drug monitoring of fluoroquinolones for patients with tuberculosis.

PMID: 33317915 [PubMed - as supplied by publisher]

Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.

Stroke. 2020 Dec 15;:STROKEAHA119028687

Authors: Heitsch L, Ibanez L, Carrera C, Binkley MM, Strbian D, Tatlisumak T, Bustamante A, Ribó M, Molina C, Dávalos A, López-Cancio E, Muñoz-Narbona L, Soriano-Tárraga C, Giralt-Steinhauer E, Obach V, Slowik A, Pera J, Lapicka-Bodzioch K, Derbisz J, Sobrino T, Castillo J, Campos F, Rodríguez-Castro E, Arias-Rivas S, Segura T, Serrano-Heras G, Vives-Bauza C, Díaz-Navarro R, Tur S, Jimenez C, Martí-Fàbregas J, Delgado-Mederos R, Arenillas J, Krupinski J, Cullell N, Torres-Aguila NP, Muiño E, Cárcel-Márquez J, Moniche F, Cabezas JA, Ford AL, Dhar R, Roquer J, Khatri P, Jiménez-Conde J, Fernandez-Cadenas I, Montaner J, Rosand J, Cruchaga C, Lee JM, International Stroke Genetics Consortium

Abstract
BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes.
METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA).
RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes.
CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

PMID: 33317415 [PubMed - as supplied by publisher]

Development of a Pharmacogenetic Lab-on-Chip Assay Based on the In-Check Technology to Screen for Genetic Variations Associated to Adverse Drug Reactions to Common Chemotherapeutic Agents.

Biosensors (Basel). 2020 Dec 09;10(12):

Authors: Iemmolo R, La Cognata V, Morello G, Guarnaccia M, Arbitrio M, Alessi E, Cavallaro S

Abstract
BACKGROUND: Antineoplastic agents represent the most common class of drugs causing Adverse Drug Reactions (ADRs). Mutant alleles of genes coding for drug-metabolizing enzymes are the best studied individual risk factors for these ADRs. Although the correlation between genetic polymorphisms and ADRs is well-known, pharmacogenetic tests are limited to centralized laboratories with expensive or dedicated instrumentation used by specialized personnel. Nowadays, DNA chips have overcome the major limitations in terms of sensibility, specificity or small molecular detection, allowing the simultaneous detection of several genetic polymorphisms with time and costs-effective advantages. In this work, we describe the design of a novel silicon-based lab-on-chip assay able to perform low-density and high-resolution multi-assay analysis (amplification and hybridization reactions) on the In-Check platform.
METHODS: The novel lab-on-chip was used to screen 17 allelic variants of three genes associated with adverse reactions to common chemotherapeutic agents: DPYD (Dihydropyrimidine dehydrogenase), MTHFR (5,10-Methylenetetrahydrofolate reductase) and TPMT (Thiopurine S-methyltransferase).
RESULTS: Inter- and intra assay variability were performed to assess the specificity and sensibility of the chip. Linear regression was used to assess the optimal hybridization temperature set at 52 °C (R2 ≈ 0.97). Limit of detection was 50 nM.
CONCLUSIONS: The high performance in terms of sensibility and specificity of this lab-on-chip supports its further translation to clinical diagnostics, where it may effectively promote precision medicine.

PMID: 33317085 [PubMed - in process]

32 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/12/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

31 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/12/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Neurophysiological biomarkers using transcranial magnetic stimulation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis.

Neurosci Biobehav Rev. 2020 Dec 08;:

Authors: Mimura Y, Nishida H, Nakajima S, Tsugawa S, Morita S, Yoshida K, Tarumi R, Ogyu K, Wada M, Kurose S, Miyazaki T, Blumberger DM, Daskalakis ZJ, Chen R, Mimura M, Noda Y

Abstract
Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with AD, mild cognitive impairment (MCI), and healthy controls (HC). Our meta-analyses indicated that RMT, SAI, SICI, and LICI were significantly lower in patients with AD, while ICF did not show a difference in patients with AD compared with HC. In patients with MCI, RMT and SAI were significantly lower than in HC. In conclusion, motor cortical excitability was increased, while cholinergic function was decreased in AD and MCI in comparison with HC and patients with AD had decreased GABAergic and glutamatergic functions compared with HC. Our results warrant further studies to differentiate AD, MCI, and HC, employing multimodal TMS neurophysiology.

PMID: 33307047 [PubMed - as supplied by publisher]

Rethinking Clinical Trials and Personalized Medicine with Placebogenomics and Placebo Dose.

OMICS. 2020 Dec 10;:

Authors: Özdemir V, Endrenyi L

Abstract
Pharmacogenomics, nutrigenomics, vaccinomics, and the nascent field of plant omics are examples of variability science. They are embedded within an overarching framework of personalized medicine. Across these public health specialties, the significance and biology of the placebo response have been historically neglected. A placebo is any substance such as a sugar pill administered in the guise of medication, but one that does not have pharmacological activity. Placebos do have clinical effects, however, that can be substantive in magnitude and vary markedly from person-to-person depending, for example, on the type of disease, symptoms, or clinical trial design. Research over the past several decades attests to a genuine neurobiological basis for placebo effects. All drugs have placebo components that contribute to their overall treatment effect. Placebos are used in clinical trials as control groups to ascertain the net pharmacological effect of a drug candidate. Not only less well known but also relevant to rational therapeutics and personalized medicine is the nocebo. A nocebo effect occurs when an inert substance is administered in a context that induces negative expectations, worsening patients' symptoms. With the COVID-19 pandemic, there are high public expectations for new vaccines and medicines to end the contagion, while at the same time antiscience, post-truth, and antivaccine movements are worrisomely on the rise. These social movements, changes in public health cultures, and conditioned behavioral responses can trigger both placebo and nocebo effects. Hence, in clinical trials, forecasting and explaining placebo and nocebo variability are more important than ever for robust science and personalized health care. Against this overarching context, this article provides (1) a brief history of placebo and (2) a discussion on biology, mechanisms, and variability of placebo effects, and (3) discusses three emerging new concepts: placebogenomics, nocebogenomics, and augmented placebo, that is, the notion of a "placebo dose." We conclude with a roadmap for placebogenomics, its synergies with the nascent field of social pharmacology, and the ways in which a new taxonomy of drug and placebo variability can be anticipated in the next decade.

PMID: 33305994 [PubMed - as supplied by publisher]

Pharmacogenetics of inflammatory bowel disease.

Pharmacogenomics. 2020 Dec 11;:

Authors: van den Bosch BJ, Coenen MJ

Abstract
Patients with inflammatory bowel disease (IBD) show large variability in disease course, and also treatment response. The variability in treatment response has led to many initiatives in search of genetic markers to optimize treatment and avoid severe side effects. This has been very successful for thiopurines, one of the drugs used to induce and maintain remission in IBD. However, for the newer treatment options for IBD, like biologicals, the search for genetic predictors has not yielded any candidate biomarkers with clinical utility. In this review, a summary of recent advances in pharmacogenetics focusing on thiopurines and anti-TNF agents is given.

PMID: 33305616 [PubMed - as supplied by publisher]

Indo-Swiss symposium on advances in pharmacogenomic strategies for implementation of personalized medicine.

Pharmacogenomics. 2020 Dec 11;:

Authors: Xaviar S, Kumar S, Ramasamy K, Chakradhara Rao US

Abstract
The Indo-Swiss symposium on advances in pharmacogenomic strategies for implementation of personalized medicine was conducted as a part of the JIPMER Integrated Pharmacogenomics Program (JIPP), held in Puducherry, India on 23 November 2019. The symposium focused on the growing contribution of pharmacogenomic information in designing treatment strategies and promoting better approaches to personalized medicine. The primary objective of this symposium was to bridge gaps in understanding the basics and recent advances in the field of pharmacogenomics. This symposium sought to promote interaction between the Indian and Swiss researchers to initiate future collaborative research projects. This symposium also served as a platform for young researchers to present their research findings as posters to the audience.

PMID: 33305611 [PubMed - as supplied by publisher]

Case report: severe toxicity in an African-American patient receiving FOLFOX carrying uncommon allelic variants in DPYD.

Pharmacogenomics. 2020 Dec 11;:

Authors: Sissung TM, Cordes L, Peer CJ, Gandhy S, Redman J, Strauss J, Figg WD

Abstract
Cancers of the colon are commonly treated with fluoropyrimidines, which often cause severe toxicities in patients with certain variants in DPYD. Y186C (rs115232898) and a variant in the 3' untranslated region (rs12132152) are uncommon alleles previously observed in African-Americans. An African-American female underwent 5-fluorouracil-based therapy (400 mg/m2 bolus, 1200 mg/m2/day over 46 h). The patient experienced severe pancytopenia after the first cycle. After 5-fluorouracil (5-FU) dose reduction (600 mg/m2/day), the steady-state 5-FU plasma concentration became 474 ng/ml (range 301-619 ng/ml) and increased following a subsequence dose increase (800 mg/m2/day; 1248 ng/ml). After a 1000 mg/m2/day dose resulted in myelosuppression, 5-FU was again de-escalated for the remaining cycles (600 mg/m2). The observed complications are likely a function of uncommon genetic variants that affect DPYD metabolism.

PMID: 33305610 [PubMed - as supplied by publisher]

Genome-wide association study of asthma exacerbations despite inhaled corticosteroids use.

Eur Respir J. 2020 Dec 10;:

Authors: Hernandez-Pacheco N, Vijverberg SJ, Herrera-Luis E, Li J, Sio YY, Granell R, Corrales A, Maroteau C, Lethem R, Perez-Garcia J, Farzan N, Repnik K, Gorenjak M, Soares P, Karimi L, Schieck M, Pérez-Méndez L, Berce V, Tavendale R, Eng C, Sardon O, Kull I, Mukhopadhyay S, Pirmohamed M, Verhamme KM, Burchard EG, Kabesch M, Hawcutt DB, Melén E, Potočnik U, Chew FT, Tantisira KG, Turner S, Palmer CN, Flores C, Pino-Yanes M, Maitland-van der Zee AH, PiCA and SysPharmPedia consortia

Abstract
RATIONALE: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.
METHODS: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 European-descent children treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.
RESULTS: Ten independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10-6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078, p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.
CONCLUSIONS: The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.

PMID: 33303529 [PubMed - as supplied by publisher]

Do Maternal Pharmacogenetics Impact the Neonatal Abstinence Syndrome Following In Utero Exposure to Antidepressant Medications?

J Obstet Gynaecol Can. 2020 Nov 05;:

Authors: Shea AK, Wang DY, Snelgrove JW, Dalfen A, Hewko S, Murphy KE

Abstract
OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used medications for mood and anxiety disorders in women. Many women need to continue or initiate these medications during pregnancy, but there is concern about potential withdrawal effects in the newborn, referred to as neonatal abstinence syndrome (NAS). The reason why some infants remain asymptomatic while others are affected has not been elucidated. The objective of this study was to examine whether genetic differences in maternal drug metabolism influence the incidence of NAS.
METHODS: Women who took Selective serotonin reuptake inhibitors s/SNRIs during pregnancy were recruited from obstetrical clinics. DNA was extracted from saliva samples for genetic analyses of cytochrome P450 (CYP) enzyme polymorphisms. Delivery and NAS data were collected from electronic medical records.
RESULTS: Ninety-five women participated. The overall NAS rate was 16.2%. Mild NAS was seen in 13.8% of neonates and severe NAS, in 2%. One-quarter (25%) of the neonates with mild withdrawal symptoms were born to mothers with polymorphisms associated with slower metabolism of their particular antidepressant, but this association was not statistically significant.
CONCLUSION: Importantly, the overall rate of NAS in our study was lower than previously reported. Maternal CYP polymorphisms did not affect the rate of NAS in neonates exposed to SSRIs/SNRIs in utero. This study lends added assurance to patients requiring SSRIs or SNRIs during pregnancy.

PMID: 33303407 [PubMed - as supplied by publisher]

An association of Myelin Oligodendrocyte Glycoprotein (MOG) gene variants with white matter volume in pediatric obsessive-compulsive disorder.

Psychiatry Res Neuroimaging. 2020 Nov 21;307:111231

Authors: Zai G, Arnold PD, Richter MA, Hanna GL, Rosenberg D, Kennedy JL

Abstract
An increasing number of neuroimaging studies have implicated alterations of white matter in obsessive-compulsive disorder (OCD). The myelin oligodendrocyte glycoprotein (MOG) gene plays a major role in myelination, and has previously demonstrated significant association with this disorder, thus variations in this gene may contribute to observed white matter alterations. The purpose of this study is to examine the relationship between white matter volume in OCD and genetic variations in the MOG gene. Two polymorphisms in the MOG gene, MOG(C1334T) and MOG(C10991T), were investigated for association with total white matter volume as measured using volumetric magnetic resonance imaging in 37 pediatric OCD patients. We compared white matter volumes between allele and genotype groups for each polymorphism using ANCOVA. A significant relationship was detected between genotype C/C of MOG(C10991T) and decreased total white matter volume (P = 0.016). Our results showed an association between a MOG genetic variant and white matter volume. This finding is intriguing in light of the posited role of white matter alteration in the etiology of at least some cases of childhood-onset OCD. Further investigation with larger samples and sub-regional white matter volume phenotypes is warranted.

PMID: 33302097 [PubMed - as supplied by publisher]

Relative addictive potential of opioid analgesic agents.

Pain Manag. 2020 Dec 10;:

Authors: Connors NJ, Mazer-Amirshahi M, Motov S, Kim HK

Abstract
Opioid overdoses and deaths continue to be a problem in the USA with a significant portion related to prescribed opioid analgesic agents. The role of pharmacogentic factors in opioid addiction is an active area of research. While all opioid analgesic agents have some addictive potential, it is clear that there are some with greater addictive potential. Oxycodone is the most widely abused opioid analgesic and it appears to predispose to chronic use with high likability by users. Fentanyl and hydromorphone are both very lipophilic allowing rapid penetration into the CNS, but are not rated as highly as other agents. Providers should consider the risk of addiction with the opioids they prescribe and give those with a lower addictive potential.

PMID: 33300384 [PubMed - as supplied by publisher]

Transferability Of Ancestry-Specific And Cross-Ancestry CYP2A6 Activity Genetic Risk Scores In African And European Populations.

Clin Pharmacol Ther. 2020 Dec 09;:

Authors: El-Boraie A, Chenoweth MJ, Pouget JG, Benowitz NL, Fukunaga K, Mushiroda T, Kubo M, Nollen NL, Cox LS, Lerman C, Knight J, Tyndale RF

Abstract
The Nicotine Metabolite Ratio (NMR, 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in non-, former- or intermittent-smokers, for example in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European-ancestry populations (EUR) by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study we developed and replicated an African-ancestry (AFR) wGRS which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.

PMID: 33300144 [PubMed - as supplied by publisher]

Antioxidants Targeting Mitochondrial Oxidative Stress: Promising Neuroprotectants for Epilepsy.

Oxid Med Cell Longev. 2020;2020:6687185

Authors: Yang N, Guan QW, Chen FH, Xia QX, Yin XX, Zhou HH, Mao XY

Abstract
Mitochondria are major sources of reactive oxygen species (ROS) within the cell and are especially vulnerable to oxidative stress. Oxidative damage to mitochondria results in disrupted mitochondrial function and cell death signaling, finally triggering diverse pathologies such as epilepsy, a common neurological disease characterized with aberrant electrical brain activity. Antioxidants are considered as promising neuroprotective strategies for epileptic condition via combating the deleterious effects of excessive ROS production in mitochondria. In this review, we provide a brief discussion of the role of mitochondrial oxidative stress in the pathophysiology of epilepsy and evidences that support neuroprotective roles of antioxidants targeting mitochondrial oxidative stress including mitochondria-targeted antioxidants, polyphenols, vitamins, thiols, and nuclear factor E2-related factor 2 (Nrf2) activators in epilepsy. We point out these antioxidative compounds as effectively protective approaches for improving prognosis. In addition, we specially propose that these antioxidants exert neuroprotection against epileptic impairment possibly by modulating cell death interactions, notably autophagy-apoptosis, and autophagy-ferroptosis crosstalk.

PMID: 33299529 [PubMed - in process]

Prevalence and types of inconsistencies in clinical pharmacogenetic recommendations among major U.S. sources.

NPJ Genom Med. 2020 Oct 30;5(1):48

Authors: Shugg T, Pasternak AL, London B, Luzum JA

Abstract
Clinical implementation of pharmacogenomics (PGx) is slow. Previous studies have identified some inconsistencies among clinical PGx recommendations, but the prevalence and types of inconsistencies have not been comprehensively analyzed among major PGx guidance sources in the U.S. PGx recommendations from the Clinical Pharmacogenetics Implementation Consortium, U.S. Food and Drug Administration drug labels, and major U.S. professional medical organizations were analyzed through May 24, 2019. Inconsistencies were analyzed within the following elements: recommendation category; whether routine screening was recommended; and the specific biomarkers, variants, and patient groups involved. We identified 606 total clinical PGx recommendations, which contained 267 unique drugs. Composite inconsistencies occurred in 48.1% of clinical PGx recommendations overall, and in 93.3% of recommendations from three sources. Inconsistencies occurred in the recommendation category (29.8%), the patient group (35.4%), and routine screening (15.2%). In conclusion, almost one-half of clinical PGx recommendations from prominent U.S. guidance sources contain inconsistencies, which can potentially slow clinical implementation.

PMID: 33298916 [PubMed]

HLA-Cw6 and other HLA-C alleles, as well as MICB-DT, DDX58 and TYK2 genetic variants associate with optimal response to anti-IL-17A treatment in patients with psoriasis.

Expert Opin Biol Ther. 2020 Dec 09;:

Authors: Morelli M, Galluzzo M, Madonna S, Scarponi C, Scaglione GL, Galluccio T, Andreani M, Pallotta S, Girolomoni G, Bianchi L, Talamonti M, Albanesi C

Abstract
OBJECTIVE: Our pharmacogenomic study evaluated the influence of the presence/absence of genetic variants of psoriasis-risk loci on the clinical response to secukinumab. Differences in the single-nucleotide polymorphism (SNP) pattern characterizing HLA-Cw6+ or HLA-Cw6- patient subpopulations, showing high or low responses to secukinumab, were also analysed.
METHODS: 417 SNPs were analyzed by Next-Generation Sequencing technology, in a cohort of 62 psoriatic patients and undergone secukinumab treatment.
Univariate regression analysis was employed to examine the association between SNP and clinical response to secukinumab. Multivariate analysis was also performed to assess multivariate differences in SNP pattern of HLA-Cw6+ or HLA-Cw6- patients showing high or low responses to secukinumab.
RESULTS: Eight SNPs in HLA-C and upstream region (rs13207315, rs6900444, rs12189871, rs12191877, rs4406273, and rs10484554), including HLA-Cw6 classical allele (rs1131118), and three in MICB-DT (rs9267325), DDX58 (rs34085293) and TYK2 (rs2304255) genes, associating with excellent response to secukinumab were identified. Importantly, rs34085293 or rs2304255 SNP status defined a subgroup of super-responder patients. We also found that HLA-Cw6+ and HLA-Cw6- patients carried out specific patterns of SNPs associating with different responses to secukinumab.
CONCLUSION: Assessment of HLA-Cw6, together with other allelic variants of genes, could be helpful to define patients which better benefit from anti-IL-17 therapy.

PMID: 33297781 [PubMed - as supplied by publisher]

Quantile-specific heritability of total cholesterol and its pharmacogenetic and nutrigenetic implications.

Int J Cardiol. 2020 Dec 06;:

Authors: Williams PT

Abstract
BACKGROUND: "Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. cholesterol) is high or low relative to its distribution. We have previously shown that the effect of a 52-SNP genetic-risk score was 3-fold larger at the 90th percentile of the total cholesterol distribution than at its 10th percentile. The objective of this study is to assess quantile-dependent expressivity for total cholesterol in 7006 offspring with parents and 2112 sibships from Framingham Heart Study.
METHODS: Quantile-specific heritability (h2) was estimated as twice the offspring-parent regression slope as robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples.
RESULTS: Quantile-specific h2 increased linearly with increasing percentiles of the offspring's cholesterol distribution (P = 3.0 × 10-9), i.e. h2 = 0.38 at the 10th percentile, h2 = 0.45 at the 25th percentile, h2 = 0.52 at the 50th, h2 = 0.61 at the 75th percentile, and h2 = 0.65 at the 90th percentile of the total cholesterol distribution. Average h2 decreased from 0.55 to 0.34 in 3564 offspring who started cholesterol-lowering medications, but this was attributable to quantile-dependent expressivity and the offspring's 0.94 mmol/L average drop in total cholesterol. Quantile-dependent expressivity likely explains the reported effect of the CELSR2/PSRC1/SORT1 rs646776 and APOE rs7412 gene loci on statin efficacy. Specifically, a smaller genetic effect size at the lower (post-treatment) than higher (pre-treatment) cholesterol concentrations mandates that the trajectories of the genotypes cannot move in parallel when cholesterol is decreased pharmacologically.
CONCLUSION: Cholesterol concentrations exhibit quantile-dependent expressivity, which may provide an alternative interpretation to pharmacogenetic and nutrigenetic interactions.

PMID: 33296721 [PubMed - as supplied by publisher]