Associations between the 1438A/G, 102T/C, and rs7997012G/A polymorphisms of HTR2A and the safety and efficacy of antidepressants in depression: a meta-analysis.

Pharmacogenomics J. 2020 Oct 23;:

Authors: Wan YS, Zhai XJ, Tan HA, Ai YS, Zhao LB

Abstract
The correlations between hydroxytryptamine receptor 2A (HTR2A) gene polymorphisms (1438A/G, 102T/C, and rs7997012G/A) and the safety and efficacy of antidepressants in depression patients were constantly reported, but conclusions are debatable. This meta-analysis ascertained forty-two studies on the efficacy (including response and remission) and side-effect issued before February 2020. Pooled analyses indicated significant associations of 1438A/G polymorphism (16 studies, 1931 subjects) and higher response within dominant model (OR: 1.40, 95% CI: 1.12-1.76); rs7997012G/A polymorphism (nine studies, 1434 subjects) and higher remission in overall models (dominant model: OR: 1.30, 95% CI: 1.01-1.66; recessive model: OR: 2.20, 95% CI: 1.53-3.16; homozygote model: OR: 2.73, 95% CI: 1.78-4.17); 102T/C polymorphism (eight studies, 804 subjects) and reduced risk of side-effect within recessive (OR: 0.57, 95% CI: 0.4-0.83) and homozygote models (OR: 0.54, 95% CI: 0.29-0.99). For depression patients, genotyping of HTR2A polymorphisms is a promising tool for estimating the outcome and side-effect of antidepressants.

PMID: 33097827 [PubMed - as supplied by publisher]

Gender Differences in Genetic Associations of RAB38 with Urinary Protein-to-Creatinine Ratio (UPCR) Levels in Diabetic Nephropathy Patients.

J Pers Med. 2020 Oct 21;10(4):

Authors: Yu ZL, Wong CS, Lai YT, Chou WH, Faridah IN, Kao CC, Lin YF, Chang WC

Abstract
Renal dysfunction is common in patients with diabetes mellitus (DM). Previous findings from a meta-analysis of GWAS indicated that the variation of RAB38/CTSC is highly associated with the urinary albumin-to-creatinine ratio (UACR) in European populations. In addition, RAB38 knockout rats showed an increase in urinary albumins. Although the prevalence of chronic kidney disease is high in Taiwan, the role of genetic variants in diabetic renal function is still unclear. In the current study, 275 diabetic nephropathy (DN) patients were recruited to perform a genetic association study. Our results indicated that rs1027027, rs302647, and rs302646 in RAB38 were significantly associated with urinary protein-to-creatinine ratio (UPCR) levels in DN patients. Importantly, after analysis stratified by gender, a significant genetic influence on UPCR levels was observed in the male population. The findings confirmed the roles of gender and variants of RAB38 in the risk of UPCR in Diabetic Nephropathy patients.

PMID: 33096837 [PubMed - as supplied by publisher]

Klotho, PTSD, and advanced epigenetic age in cortical tissue.

Neuropsychopharmacology. 2020 Oct 23;:

Authors: Wolf EJ, Chen CD, Zhao X, Zhou Z, Morrison FG, Daskalakis NP, Stone A, Schichman S, Grenier JG, Fein-Schaffer D, Huber BR, Traumatic Stress Brain Research Group, Abraham CR, Miller MW, Logue MW

Abstract
This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42). An evaluation of 211 additional common KL variants revealed that only variants in linkage disequilibrium with rs9315202 showed similarly high levels of significance. Alcohol abuse was nominally associated with advanced epigenetic age in motor cortex (p = 0.039, n = 114). The rs9315202 SNP interacted with PTSD to predict decreased KL expression via DNAm age residuals in motor cortex among older white non-Hispanics decedents (indirect β = -0.198, p = 0.027). Finally, in dual-luciferase enhancer reporter system experiments, we found that inserting the minor allele of rs9315202 in a human kidney cell line HK-2 genomic DNA resulted in a change in KL transcriptional activities, likely operating via long noncoding RNA in this region. This was the first study to examine multiple forms of psychopathology in association with advanced DNA methylation age across several brain regions, to extend work concerning the association between rs9315202 and advanced epigenetic to brain tissue, and to identify the effects of rs9315202 on KL gene expression. KL augmentation holds promise as a therapeutic intervention to slow the pace of cellular aging, disease onset, and neuropathology, particularly in older, stressed populations.

PMID: 33096543 [PubMed - as supplied by publisher]

Effects of SCN1A and SCN2A polymorphisms on responsiveness to valproic acid monotherapy in epileptic children.

Epilepsy Res. 2020 Oct 11;168:106485

Authors: Liu M, Mao J, Xu H, Wang J, Zhao P, Xu Q, Du Z

Abstract
PURPOSE: This study was conducted to explore the influence of genetic variations on responsiveness to valproic acid (VPA) monotherapy among Chinese children with epilepsy.
METHODS: One hundred and forty epileptic children taking VPA as monotherapy were enrolled, and at least one-year follow-up was obtained to assess the therapeutic outcome. Twenty-seven single nucleotide polymorphisms (SNPs) within twelve candidate genes correlated with the metabolic enzymes, transporters and targets of VPA were genotyped. The effects of selected polymorphisms on VPA efficacy were identified by binary logistic regression analysis adjusting for potential confounders.
RESULTS: SCN2A rs2304016 (A > G) AG genotype was more common among the VPA-resistant patients in comparison with the VPA-responsive patients (OR = 3.18, 95 % CI = 1.10-9.14, P = 0.032), and in subgroup of focal seizure, lower frequency of VPA resistance was found in epileptic children with SCN1A rs2298771 AG genotype than those with AA genotype (OR = 0.11, 95 % CI = 0.01-0.91, P = 0.040).
CONCLUSIONS: Our study indicated that SCN2A rs2304016 and SCN1A rs2298771 polymorphisms might be associated with the response to VPA monotherapy in Chinese epileptic children. Further and larger researches are required to validate these results.

PMID: 33096315 [PubMed - as supplied by publisher]

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry. 2020 Oct 20;:

Authors: Johnson EC, Demontis D, Thorgeirsson TE, Walters RK, Polimanti R, Hatoum AS, Sanchez-Roige S, Paul SE, Wendt FR, Clarke TK, Lai D, Reginsson GW, Zhou H, He J, Baranger DAA, Gudbjartsson DF, Wedow R, Adkins DE, Adkins AE, Alexander J, Bacanu SA, Bigdeli TB, Boden J, Brown SA, Bucholz KK, Bybjerg-Grauholm J, Corley RP, Degenhardt L, Dick DM, Domingue BW, Fox L, Goate AM, Gordon SD, Hack LM, Hancock DB, Hartz SM, Hickie IB, Hougaard DM, Krauter K, Lind PA, McClintick JN, McQueen MB, Meyers JL, Montgomery GW, Mors O, Mortensen PB, Nordentoft M, Pearson JF, Peterson RE, Reynolds MD, Rice JP, Runarsdottir V, Saccone NL, Sherva R, Silberg JL, Tarter RE, Tyrfingsson T, Wall TL, Webb BT, Werge T, Wetherill L, Wright MJ, Zellers S, Adams MJ, Bierut LJ, Boardman JD, Copeland WE, Farrer LA, Foroud TM, Gillespie NA, Grucza RA, Harris KM, Heath AC, Hesselbrock V, Hewitt JK, Hopfer CJ, Horwood J, Iacono WG, Johnson EO, Kendler KS, Kennedy MA, Kranzler HR, Madden PAF, Maes HH, Maher BS, Martin NG, McGue M, McIntosh AM, Medland SE, Nelson EC, Porjesz B, Riley BP, Stallings MC, Vanyukov MM, Vrieze S, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis LK, Bogdan R, Gelernter J, Edenberg HJ, Stefansson K, Børglum AD, Agrawal A

Abstract
BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.
METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.
FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.
INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.
FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

PMID: 33096046 [PubMed - as supplied by publisher]

Coadministration of metformin prevents olanzapine-induced metabolic dysfunction and regulates the gut-liver axis in rats.

Psychopharmacology (Berl). 2020 Oct 23;:

Authors: Luo C, Wang X, Huang HX, Mao XY, Zhou HH, Liu ZQ

Abstract
OBJECTIVE: Olanzapine is widely prescribed for patients with mental disorders; however, it may induce metabolic dysfunction. Metformin is an efficient adjuvant for preventing olanzapine-induced metabolic dysfunction in clinical practice. Although the mechanism of how metformin prevents this metabolic dysfunction remains unknown, changes in the gut-liver axis are considered a potential explanation.
METHODS: Forty-eight male rats were gavaged with olanzapine and/or metformin for 35 consecutive days. Body weight, food intake, and water intake were measured daily. Histopathological and biochemical tests were performed to evaluate the metabolic dysfunction. The 16S rRNA obtained from fecal bacterial DNA was assessed.
RESULTS: Olanzapine treatment increased the body weight, blood glucose and triglyceride levels, and the number of adipocytes in the liver. While coadministration of metformin, there was a dose-dependent reverse of the abnormal changes induced by olanzapine treatment. Both olanzapine and metformin treatments altered the composition of the gut microbiota. Bacteroides acidifaciens and Lactobacillus gasseri were possibly played a positive role in metformin-mediated olanzapine-induced metabolic dysfunction prevention.
CONCLUSION: Metformin prevented olanzapine-induced metabolic dysfunction and regulated the gut microbiota in a dose-dependent manner.

PMID: 33095288 [PubMed - as supplied by publisher]

Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review.

Expert Opin Drug Metab Toxicol. 2020 Oct 23;:

Authors: Hein DW, Millner LM

Abstract
INTRODUCTION: The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs.
AREAS COVERED: We describe and review data that more clearly defines the effects of NAT2 haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole for which NAT2 phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for NAT2 phenotype-dependent dosing strategies.
EXPERT OPINION: Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust NAT2 genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.

PMID: 33094670 [PubMed - as supplied by publisher]

LRP1 polymorphisms associated with warfarin stable dose in Chinese patients: a stepwise conditional analysis.

Pharmacogenomics. 2020 Oct 23;:

Authors: Li D, Zhu H, Luo ZY, Chen Y, Song GB, Zhou XM, Yan H, Zhou HH, Zhang W, Li X

Abstract
Aim: The aim of this study was to investigate whether variability in warfarin stable dose (WSD) could be influenced by vitamin K-related polymorphisms in patients with heart valve replacement. Patients & methods: Twenty-nine vitamin K-related SNPs in 208 patients who initially took warfarin and achieved WSD were genotyped. Results: After conducting conditional analysis for both VKORC1 -1639G>A and CYP2C9*3, LRP1 rs1800139 and LRP1 rs1800154 were significantly associated with WSD (p = 0.007 and p = 0.015, respectively). Multivariate analysis showed that LRP1 rs1800139 accounted for 5.9% WSD variability. Conclusion: Our results suggest that a novel vitamin K-related gene, LRP1, exerts a relevant influence on WSD, independent of VKORC1 -1639G>A and CYP2C9*3.

PMID: 33094665 [PubMed - as supplied by publisher]

Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity.

Hum Genomics. 2020 Oct 22;14(1):40

Authors: Anastassopoulou C, Gkizarioti Z, Patrinos GP, Tsakris A

Abstract
BACKGROUND: The emergence of the novel coronavirus in Wuhan, Hubei Province, China, in December 2019 marked the synchronization of the world to a peculiar clock that is counting infected cases and deaths instead of hours and minutes. The pandemic, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has indeed caused considerable morbidity and mortality and drastically changed our everyday lives. As we continue to become acquainted with the seventh coronavirus known to infect our species, a number of its characteristics keep surprising us. Among those is the wide spectrum of clinical manifestations of the resulting coronavirus disease 2019 (COVID-19), which ranges from asymptomatic or mildly symptomatic infections to severe pneumonia, respiratory failure, and death.
MAIN BODY: Data, now from patient populations, are beginning to accumulate on human genetic factors that may contribute to the observed diversified disease severity. Therefore, we deemed it prudent to review the associations between specific human genetic variants and clinical disease severity or susceptibility to infection that have been reported in the literature to date (at the time of writing this article in early August 2020 with updates in mid-September). With this work, we hope (i) to assist the fast-paced biomedical research efforts to combat the virus by critically summarizing current knowledge on the potential role of host genetics, and (ii) to help guide current genetics and genomics research towards candidate gene variants that warrant further investigation in larger studies. We found that determinants of differing severity of COVID-19 predominantly include components of the immune response to the virus, while determinants of differing susceptibility to SARS-CoV-2 mostly entail genes related to the initial stages of infection (i.e., binding of the cell surface receptor and entry).
CONCLUSION: Elucidating the genetic determinants of COVID-19 severity and susceptibility to SARS-CoV-2 infection would allow for the stratification of individuals according to risk so that those at high risk would be prioritized for immunization, for example, if or when safe and effective vaccines are developed. Our enhanced understanding of the underlying biological mechanisms could also guide personalized therapeutics. Such knowledge is already beginning to provide clues that help explain, at least in part, current epidemiologic observations regarding the typically more severe or benign disease course in older males and children, respectively.

PMID: 33092637 [PubMed - in process]

Synthesis of Benzimidazole-Based Analogs as Anti Alzheimer's Disease Compounds and Their Molecular Docking Studies.

Molecules. 2020 Oct 20;25(20):

Authors: Adalat B, Rahim F, Taha M, Alshamrani FJ, Anouar EH, Uddin N, Shah SAA, Ali Z, Zakaria ZA

Abstract
We synthesized 10 analogs of benzimidazole-based thiosemicarbazide 1 (a-j) and 13 benzimidazole-based Schiff bases 2 (a-m), and characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibition activities. All the synthesized analogs showed varying degrees of acetylcholinesterase and butyrylcholinesterase inhibitory potentials in comparison to the standard drug (IC50 = 0.016 and 4.5 µM. Amongst these analogs 1 (a-j), compounds 1b, 1c, and 1g having IC50 values 1.30, 0.60, and 2.40 µM, respectively, showed good acetylcholinesterase inhibition when compared with the standard. These compounds also showed moderate butyrylcholinesterase inhibition having IC50 values of 2.40, 1.50, and 2.40 µM, respectively. The rest of the compounds of this series also showed moderate to weak inhibition. While amongst the second series of analogs 2 (a-m), compounds 2c, 2e, and 2h having IC50 values of 1.50, 0.60, and 0.90 µM, respectively, showed moderate acetylcholinesterase inhibition when compared to donepezil. Structure Aactivity Relation of both synthesized series has been carried out. The binding interactions between the synthesized analogs and the enzymes were identified through molecular docking simulations.

PMID: 33092223 [PubMed - in process]

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology.

Int J Mol Sci. 2020 Jan 17;21(2):

Authors: Fatunde OA, Brown SA

Abstract
As many novel cancer therapies continue to emerge, the field of Cardio-Oncology (or onco-cardiology) has become crucial to prevent, monitor and treat cancer therapy-related cardiovascular toxicity. Furthermore, given the narrow therapeutic window of most cancer therapies, drug-drug interactions are prevalent in the cancer population. Consequently, there is an increased risk of affecting drug efficacy or predisposing individual patients to adverse side effects. Here we review the role of cytochrome P450 (CYP450) enzymes in the field of Cardio-Oncology. We highlight the importance of cardiac medications in preventive Cardio-Oncology for high-risk patients or in the management of cardiotoxicities during or following cancer treatment. Common interactions between Oncology and Cardiology drugs are catalogued, emphasizing the impact of differential metabolism of each substrate drug on unpredictable drug bioavailability and consequent inter-individual variability in treatment response or development of cardiovascular toxicity. This inter-individual variability in bioavailability and subsequent response can be further enhanced by genomic variants in CYP450, or by modifications of CYP450 gene, RNA or protein expression or function in various 'omics' related to precision medicine. Thus, we advocate for an individualized approach to each patient by a multidisciplinary team with clinical pharmacists evaluating a treatment plan tailored to a practice of precision Cardio-Oncology. This review may increase awareness of these key concepts in the rapidly evolving field of Cardio-Oncology.

PMID: 31963461 [PubMed - indexed for MEDLINE]

Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature.

Pharmacol Ther. 2020 Oct 19;:107710

Authors: Dello Russo C, Scott KA, Pirmohamed M

Abstract
Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.

PMID: 33091427 [PubMed - as supplied by publisher]

Correlation of body weight and composition with hepatic activities of cytochrome P450 enzymes.

J Pharm Sci. 2020 Oct 19;:

Authors: Krogstad V, Peric A, Robertsen I, Kringen MK, Vistnes M, Hjelmesæth J, Sandbu R, Johnson LK, Angeles PC, Jansson-Löfmark R, Karlsson C, Andersson S, Åsberg A, Andersson TB, Christensen H

Abstract
Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m2 were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CLint,u) values for CYP3A correlated negatively with body weight (r=-0.43, p<0.01), waist circumference (r=-0.47, p<0.01), hip circumference (r=-0.51, p<0.01), fat percent (r=-0.41, p<0.05), fat mass (r=-0.48, p<0.01) and BMI (r=-0.46, p<0.01). Linear regression analysis showed that CLint,u values for CYP3A decreased with 5 % with each 10 % increase in body weight (r2=0.12, β=-0.558, p<0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.

PMID: 33091408 [PubMed - as supplied by publisher]

Longitudinal trajectory analysis of antipsychotic response in patients with schizophrenia: 6-week, randomised, open-label, multicentre clinical trial.

BJPsych Open. 2020 Oct 22;6(6):e126

Authors: Dai M, Wu Y, Tang Y, Yue W, Yan H, Zhang Y, Tan L, Deng W, Chen Q, Yang G, Lu T, Wang L, Yang F, Zhang F, Yang J, Li K, Lv L, Tan Q, Zhang H, Ma X, Li L, Wang C, Ma X, Zhang D, Yu H, Zhao L, Ren H, Wang Y, Hu X, Zhang G, Du X, Wang Q, Li T, Chinese Antipsychotics Pharmacogenomics Consortium

Abstract
BACKGROUND: Understanding the patterns of treatment response is critical for the treatment of patients with schizophrenia; one way to achieve this is through using a longitudinal dynamic process study design.
AIMS: This study aims to explore the response trajectory of antipsychotics and compare the treatment responses of seven different antipsychotics over 6 weeks in patients with schizoprenia (trial registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934).
METHOD: Data were collected from a multicentre, randomised open-label clinical trial. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up at weeks 2, 4 and 6. Trajectory groups were classified by the method of k-means cluster modelling for longitudinal data. Trajectory analyses were also employed for the seven antipsychotic groups.
RESULTS: The early treatment response trajectories were classified into a high-trajectory group of better responders and a low-trajectory group of worse responders. The results of trajectory analysis showed differences compared with the classification method characterised by a 50% reduction in PANSS scores at week 6. A total of 349 patients were inconsistently grouped by the two methods, with a significant difference in the composition ratio of treatment response groups using these two methods (χ2 = 43.37, P < 0.001). There was no differential contribution of high- and low trajectories to different drugs (χ2 = 12.52, P = 0.051); olanzapine and risperidone, which had a larger proportion in the >50% reduction at week 6, performed better than aripiprazole, quetiapine, ziprasidone and perphenazine.
CONCLUSIONS: The trajectory analysis of treatment response to schizophrenia revealed two distinct trajectories. Comparing the treatment responses to different antipsychotics through longitudinal analysis may offer a new perspective for evaluating antipsychotics.

PMID: 33090091 [PubMed - as supplied by publisher]

Pharmacogenomics Biomarker Discovery and Validation for Translation in Clinical Practice.

Clin Transl Sci. 2020 Oct 22;:

Authors: Arbitrio M, Scionti F, Di Martino MT, Caracciolo D, Pensabene L, Tassone P, Tagliaferri P

Abstract
Interindividual variability in drug efficacy and toxicity is a major challenge in clinical practice. Variations in drug pharmacokinetics (PKs) and pharmacodynamics (PDs) can be, in part, explained by polymorphic variants in genes encoding drug metabolizing enzymes and transporters (absorption, distribution, metabolism, and excretion) or in genes encoding drug receptors. Pharmacogenomics (PGx) has allowed the identification of predictive biomarkers of drug PKs and PDs and the current knowledge of genome-disease and genome-drug interactions offers the opportunity to optimize tailored drug therapy. High-throughput PGx genotyping, from targeted to more comprehensive strategies, allows the identification of PK/PD genotypes to be developed as clinical predictive biomarkers. However, a biomarker needs a robust process of validation followed by clinical-grade assay development and must comply to stringent regulatory guidelines. We here discuss the methodological challenges and the emerging technological tools in PGx biomarker discovery and validation, at the crossroad among molecular genetics, bioinformatics, and clinical medicine.

PMID: 33089968 [PubMed - as supplied by publisher]

Association of FMO3 rs1736557 polymorphism with clopidogrel response in Chinese patients with coronary artery disease.

Eur J Clin Pharmacol. 2020 Oct 21;:

Authors: Zhu KX, Song PY, He-Li, Li MP, Du YX, Ma QL, Peng LM, Chen XP

Abstract
PURPOSE: Dual antiplatelet therapy with aspirin and clopidogrel is commonly used for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention to prevent stent thrombosis and ischemic events. However, some patients show high on-treatment platelet reactivity (HTPR) during clopidogrel therapy. Genetic factors such as loss-of-function variants of CYP2C19 are validated to increase the risk of HTPR. Flavin-containing monooxygenase 3 (FMO3) is reported to be associated with potency of platelet responsiveness and thrombosis. This study aimed to explore the association between FMO3 rs1736557 polymorphism and clopidogrel response.
METHODS: Five hundred twenty-two Chinese CAD patients treated with dual antiplatelet therapy were recruited from Xiangya Hospital. After oral administration of 300 mg loading dose (LD) clopidogrel for 12-24 h or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days, the platelet reaction index (PRI) was determined by vasodilator-stimulated phosphoprotein-phosphorylation assay. FMO3 rs1736557, CYP2C19*2, and CYP2C19*3 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS: Mean PRI value was significantly higher in CYP2C19 poor metabolizers (PMs) and intermediate metabolizers (IMs) than the extensive metabolizers (EMs) (p < 0.001). In addition, FMO3 rs1736557 AA homozygotes showed significantly lower PRI as compared with carriers of the major rs1736557 G allele in the entire cohort and in the MD cohort (p = 0.011, p = 0.008, respectively). The risk of HTPR was decreased significantly in carriers of the rs1736557 A allele (AA vs GG: OR = 0.316, 95% CI: 0.137-0.726, p = 0.005; AA vs GA: OR = 0.249, 95% CI: 0.104-0.597, p = 0.001; AA vs GG+GA: OR = 0.294, 95% CI: 0.129-0.669, p = 0.002), and the association was observed mainly in patients carrying the CYP2C19 LOF allele and in those administered with MD.
CONCLUSION: The FMO3 rs1736557 AA genotype was related to an increased the antiplatelet potency of clopidogrel in Chinese CAD patients. Additional studies are required to verify this finding.

PMID: 33089397 [PubMed - as supplied by publisher]

DBCSMOTE: a clustering-based oversampling technique for data-imbalanced warfarin dose prediction.

BMC Med Genomics. 2020 Oct 22;13(Suppl 10):152

Authors: Tao Y, Zhang Y, Jiang B

Abstract
BACKGROUND: Vitamin K antagonist (warfarin) is the most classical and widely used oral anticoagulant with assuring anticoagulant effect, wide clinical indications and low price. Warfarin dosage requirements of different patients vary largely. For warfarin daily dosage prediction, the data imbalance in dataset leads to inaccurate prediction on the patients of rare genotype, who usually have large stable dosage requirement. To balance the dataset of patients treated with warfarin and improve the predictive accuracy, an appropriate partition of majority and minority groups, together with an oversampling method, is required.
METHOD: To solve the data-imbalance problem mentioned above, we developed a clustering-based oversampling technique denoted as DBCSMOTE, which combines density-based spatial clustering of application with noise (DBCSCAN) and synthetic minority oversampling technique (SMOTE). DBCSMOTE automatically finds the minority groups by acquiring the association between samples in terms of the clinical features/genotypes and the warfarin dosage, and creates an extended dataset by adding the new synthetic samples of majority and minority groups. Meanwhile, two ensemble models, boosted regression tree (BRT) and random forest (RF), which are built on the extended dataset generateed by DBCSMOTE, accomplish the task of warfarin daily dosage prediction.
RESULTS: DBCSMOTE and the comparison methods were tested on the datasets derived from our Hospital and International Warfarin Pharmacogenetics Consortium (IWPC). As the results, DBCSMOTE-BRT obtained the highest R-squared (R2) of 0.424 and the smallest mean squared error (mse) of 1.08. In terms of the percentage of patients whose predicted dose of warfarin is within 20% of the actual stable therapeutic dose (20%-p), DBCSMOTE-BRT can achieve the largest value of 47.8% among predictive models. The more important thing is that DBCSMOTE saved about 68% computational time to achieve the same or better performance than the Evolutionary SMOTE, which was the best oversampling method in warfarin dose prediction by far. Meanwhile, in warfarin dose prediction, it is discovered that DBCSMOTE is more effective in  integrating BRT than RF  for warfarin dose prediction.
CONCLUSION: Our finding is that the genotypes, CYP2C9 and VKORC1, no doubt contribute to the predictive accuracy. It was also discovered left atrium diameter, glutamic pyruvic transaminase and serum creatinine included in the model actually improved the predictive accuracy; When congestive heart failure, diabetes mellitus and valve replacement were absent in DBCSMOTE-BRT/RF, the predictive accuracy of DBCSMOTE-BRT/RF decreased. The oversampling ratio and number of minority clusters have a large impact on the effect of oversampling. According to our test, the predictive accuracy was high when the number of minority clusters was 6 ~ 8. The oversampling ratio for small minority clusters should be large (> 1.2) and for large minority clusters should be small (< 0.2). If the dataset becomes larger, the DBCSMOTE would be re-optimized and its BRT/RF model should be re-trained. DBCSMOTE-BRT/RF outperformed the current commonly-used tool called Warfarindosing. As compared to Evolutionary SMOTE-BRT and RF  models, DBCSMOTE-BRT and RF models take only a small computational time to achieve the same or higher performance in many cases. In terms of predictive accuracy, RF is not as good as BRT. However, RF still has a powerful ability in generating a highly accurate model as the dataset increases; the software "WarfarinSeer v2.0" is a test version, which packed DBCSMOTE-BRT/RF. It could be a convenient tool for clinical application in warfarin treatment.

PMID: 33087117 [PubMed - in process]

SREBP1 as a potential biomarker predicts levothyroxine efficacy of differentiated thyroid cancer.

Biomed Pharmacother. 2020 Mar;123:109791

Authors: Li C, Peng X, Lv J, Zou H, Liu J, Zhang K, Li Z

Abstract
BACKGROUND: SREBP1 is a well-known transcript factor regulating lipogenesis. It has been reported to play an important role in tumor progress in recent years. However, the roles of SREBP1 in differentiated thyroid cancer (DTC) are uncertain. Based on this, we aimed to investigate the expression of SREBP1 and the influence of SREBP1 on DTC patients.
METHODS: qRT-PCR and immunohistochemistry were used to detect the expression of SREBPs in DTC tissues and the adjacent normal tissues. The following methods, including the MTS, colony-forming assay, flow cytometry and Hoechst staining were used to detect the biological function of thyroid cancer cells based on SREBP1 interference or not.
RESULTS: the expression of SREBP1 was significantly different among DTCs, thyroid nodules and the adjacent normal tissues. Briefly, SREBP1 was upregulated follow with the malignancy, but there was no significant difference of SREBP2 between thyroid nodules and the adjacent normal tissues. Further, the ROC curve showed that SREBP1 has higher diagnostic value than SREBP2. SREBP1 expression was significantly related to the tumor size and lymph node metastasis in DTCs. In vitro, the proliferation of thyroid cancer cells was suppressed obviously after interfered with SREBP1, and the apoptotic cells was increased. Further, SREBP1 expression was also associated with the short-term efficacy of levothyroxine in DTC patients.
CONCLUSION: this is the first time to report that SREBP1 is an oncogene and a pro-proliferation factor in thyroid cancer, indicating that SREBP1 may serve as a potential biomarker and therapeutic target in thyroid cancer.

PMID: 31887541 [PubMed - indexed for MEDLINE]

Building a Pharmacogenomics Knowledge Model Toward Precision Medicine: Case Study in Melanoma.

JMIR Med Inform. 2020 Oct 21;8(10):e20291

Authors: Kang H, Li J, Wu M, Shen L, Hou L

Abstract
BACKGROUND: Many drugs do not work the same way for everyone owing to distinctions in their genes. Pharmacogenomics (PGx) aims to understand how genetic variants influence drug efficacy and toxicity. It is often considered one of the most actionable areas of the personalized medicine paradigm. However, little prior work has included in-depth explorations and descriptions of drug usage, dosage adjustment, and so on.
OBJECTIVE: We present a pharmacogenomics knowledge model to discover the hidden relationships between PGx entities such as drugs, genes, and diseases, especially details in precise medication.
METHODS: PGx open data such as DrugBank and RxNorm were integrated in this study, as well as drug labels published by the US Food and Drug Administration. We annotated 190 drug labels manually for entities and relationships. Based on the annotation results, we trained 3 different natural language processing models to complete entity recognition. Finally, the pharmacogenomics knowledge model was described in detail.
RESULTS: In entity recognition tasks, the Bidirectional Encoder Representations from Transformers-conditional random field model achieved better performance with micro-F1 score of 85.12%. The pharmacogenomics knowledge model in our study included 5 semantic types: drug, gene, disease, precise medication (population, daily dose, dose form, frequency, etc), and adverse reaction. Meanwhile, 26 semantic relationships were defined in detail. Taking melanoma caused by a BRAF gene mutation into consideration, the pharmacogenomics knowledge model covered 7 related drugs and 4846 triples were established in this case. All the corpora, relationship definitions, and triples were made publically available.
CONCLUSIONS: We highlighted the pharmacogenomics knowledge model as a scalable framework for clinicians and clinical pharmacists to adjust drug dosage according to patient-specific genetic variation, and for pharmaceutical researchers to develop new drugs. In the future, a series of other antitumor drugs and automatic relation extractions will be taken into consideration to further enhance our framework with more PGx linked data.

PMID: 33084582 [PubMed]

Plasma miRNA profiles associated with stable warfarin dosage in Chinese patients.

PeerJ. 2020;8:e9995

Authors: Zhao L, Wang J, Shi S, Wu Y, Liu J, He S, Zou Y, Xie H, Ge S, Ye H

Abstract
Background: We used bioinformatic analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays to investigate the association between plasma microRNAs (miRNAs) and stable warfarin dosage in a Chinese Han population.
Methods: Bioinformatics analysis was used to screen out potential warfarin dose-associated miRNAs. Three plasma miRNAs were validated in 99 samples by RT-qPCR. Kruskal-Wallis test and multivariate logistic regression were used to compare differences in plasma miRNAs expression levels between three warfarin dosage groups.
Results: There were significant between-group differences among the three dose groups for hsa-miR-133b expression (p = 0.005), but we observed an "n-shaped" dose-dependent curve rather than a linear relationship. Expression levels of hsa-miR-24-3p (p = 0.475) and hsa-miR-1276 (p = 0.558) were not significantly different in the multivariate logistic regression.
Conclusion: miRNAs have received extensive attention as ideal biomarkers and possible therapeutic targets for various diseases. However, they are not yet widely used in precision medicine. Our results indicate that hsa-miR-133b may be a possible reference factor for the warfarin dosage algorithm. These findings emphasize the importance of a comprehensive evaluation of complex relationships in warfarin dose prediction models and provide new avenues for future pharmacogenomics studies.

PMID: 33083118 [PubMed]