Publications by authors named "Taisei Mushiroda"

132 Publications

Functional Characterization Of Novel Rare CYP2A6 Variants And Potential Implications For Clinical Outcomes.

Clin Transl Sci 2021 Sep 3. Epub 2021 Sep 3.

Department of Pharmacology & Toxicology, University of Toronto; 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Division of Brain and Therapeutics, 100 Stokes Street, Toronto, ON, M6J 1H4, Canada.

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviours, including cessation and smoking-related disease risk. The heritability of the NMR is 60-80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30-35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein-coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain-of-function to loss-of-function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein-coding variants (i.e. the residuals were reduced), and approximately one-third of these individuals (12/39) were reassigned from normal to slow metabolizer status. Rare coding variants can alter an individual's CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into non-coding variants is warranted to further explain the missing heritability in the NMR.
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http://dx.doi.org/10.1111/cts.13135DOI Listing
September 2021

Pharmacogenomics variants are associated with BMI differences between individuals with bipolar and other psychiatric disorders.

Pharmacogenomics 2021 Aug 19;22(12):749-760. Epub 2021 Aug 19.

Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.

Regardless of the plethora of next-generation sequencing studies in the field of pharmacogenomics (PGx), the potential effect of covariate variables on PGx response within deeply phenotyped cohorts remains unexplored. We explored with advanced statistical methods the potential influence of BMI, as a covariate variable, on PGx response in a Greek cohort with psychiatric disorders. Nine PGx variants within , , , and were associated with altered BMI in different psychiatric disorder groups. Carriers of rs2070959 (), rs199861210 () and rs2297595 () were also characterized by significant changes in the mean BMI, depending on the presence of psychiatric disorders. Specific PGx variants are significantly associated with BMI in a Greek cohort with psychiatric disorders.
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http://dx.doi.org/10.2217/pgs-2021-0012DOI Listing
August 2021

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias: genetics in inguinal hernias.

EBioMedicine 2021 Aug 12;70:103532. Epub 2021 Aug 12.

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan; Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan; The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address:

Background: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations.

Methods: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings.

Findings: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias.

Interpretation: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia.

Funding: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001).
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http://dx.doi.org/10.1016/j.ebiom.2021.103532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374389PMC
August 2021

Effect of 5-fluorouracil on mRNA expression of drug metabolizing enzyme and transporter genes in human hepatoma cell lines.

Biomed Res 2021 ;42(4):121-127

Department of Pharmacy, University of the Ryukyus Hospital.

Fluoropyrimidines such as 5-fluorouracil (5-FU) are well known to have drug-drug interactions with anticoagulant medications such as warfarin. This study investigated the mRNA expression of pharmacokinetic (PK)-related genes in response to 5-FU using the hepatocarcinoma cell lines after examining relevant gene expression via RNA sequencing. We used HepaRG cells for 5-FU treatment analysis because these cells displayed PK-related gene expression. 5-FU exposure significantly reduced cytochrome P450 3A4 (CYP3A4) mRNA expression. Additionally, the mRNA expression of nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor), a nuclear receptor transcription factor that promotes the expression of many CYP genes, was also decreased in HepaRG cells following 5-FU treatment. The mRNA expressions of the CYP2B6 and ATP-binding cassette transporter genes were decreased after 5-FU treatment. This study revealed that 5-FU treatment reduced PK-related gene expression in HepaRG cells. These findings should be useful for further drug-drug interaction research.
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http://dx.doi.org/10.2220/biomedres.42.121DOI Listing
January 2021

Genome-wide association study reveals an association between the HLA-DPB102:01:02 allele and wheat-dependent exercise-induced anaphylaxis.

Am J Hum Genet 2021 08 10;108(8):1540-1548. Epub 2021 Jul 10.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10). The HLA-DPB102:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10). A meta-analysis performed in the combined set revealed that the HLA-DPB102:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10). Individuals carrying the HLA-DPB102:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387458PMC
August 2021

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK.

Transl Psychiatry 2021 07 7;11(1):362. Epub 2021 Jul 7.

Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm and 500/mm) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.
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http://dx.doi.org/10.1038/s41398-021-01487-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260588PMC
July 2021

, , and genetic polymorphisms and their associations with susceptibility to antituberculosis drug-induced liver injury in Thai tuberculosis patients.

Heliyon 2021 Apr 20;7(4):e06852. Epub 2021 Apr 20.

Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of s polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between s and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of and genes. genotyping data were derived from microarray data. We illustrated that null and / dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, null and / dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, null and / dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082558PMC
April 2021

Functional Characterization of the Effects of -acetyltransferase 2 Alleles on -acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity.

Front Genet 2021 18;12:652704. Epub 2021 Mar 18.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in -acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated kinetic parameters of four NAT2 alleles (NAT24, 5, 6, and 7) for -acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT25, 6, and 7 exhibited significantly reduced -acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT24. Hierarchical clustering analysis revealed that 10 genotypes were categorized into three or four clusters. According to the results of metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05-54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
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http://dx.doi.org/10.3389/fgene.2021.652704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012690PMC
March 2021

Characteristics of adverse drug reactions associated with antiepileptics at a tertiary children's hospital in Japan: A retrospective observational cohort study.

Epilepsy Res 2021 Jul 11;173:106614. Epub 2021 Mar 11.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.

Objective: The aim of this study was to explore the prescription pattern of antiepileptics and the relationship between antiepileptics and adverse drug reactions (ADRs) in a Japanese population.

Methods: A retrospective observational cohort study was conducted by reviewing the medical records of patients who visited or were admitted to a single tertiary care center between January 2011 and June 2019, were treated with antiepileptics, and developed allergic ADRs associated with these drugs.

Results: In total, 14,230 unique patients received antiepileptics during the study period. Diazepam was the most frequently used antiepileptic drug (74.8 %), followed by phenobarbital (14.3 %), valproic acid (11.4 %), fosphenytoin (10.0 %), and carbamazepine (7.3 %). Although a trend of increasing prevalence of newer generation antiepileptics was noted, most patients are still treated with older generation antiepileptics. Thirty-two (0.22 %) unique patients experienced ADRs associated with antiepileptics, and the antiepileptic drug most frequently associated with ADRs was carbamazepine, at a rate of 1.4 %. Three patients developed Stevens-Johnson syndrome/toxic epidermal necrolysis, in two of which carbamazepine was implicated. Most patients experienced ADRs associated with aromatic antiepileptics (84.4 %) or older generation antiepileptics (81.3 %).

Significance: This is the first study to assess the relationship between ADRs and antiepileptics at a tertiary care center in Japan. Based on our results, most patients were prescribed older generation antiepileptics, and most ADR events were linked to the administration of drugs in this category; thus, identification of patients at risk of developing ADRs is critical in order to prevent such events.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106614DOI Listing
July 2021

Discrepancies and similarities in the genome-informed guidance for psychiatric disorders amongst different regulatory bodies and research consortia using next generation sequencing-based clinical pharmacogenomics data.

Pharmacol Res 2021 05 9;167:105538. Epub 2021 Mar 9.

Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece; The Golden Helix Foundation, London, UK. Electronic address:

Undoubtedly, pharmacogenomics (PGx) aims in optimizing drug treatment responses whilst also improving the patients' quality of life, either via a reduction of adverse drug reactions and/or an enhancement of drug treatment efficacy. To achieve this, PGx guidance is provided by the two major regulatory bodies in a worldwide level, specifically the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and occasionally some research consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Dutch Pharmacogenomics Working Group (DPWG). However, so far, there is a limited number of studies focusing on the delineation of the similarities and more importantly, the discrepancies in the PGx guidance by the different regulatory bodies and consortia. Herein, we use real-life clinical PGx data to highlight such discrepancies and similarities for genome-guided interventions in psychiatric disorders, thus demonstrating the need for harmonization of the guidelines and recommendations. More precisely, we used the PharmCAT genome-informed drug treatment reports from 304 Greek individuals with psychiatric disorders in order to emphasize on the discrepancies in the PGx guidance/guidelines between FDA vs EMA and CPIC vs DPWG, respectively. For example, CYP2D6-pimozide pair is characterized as 'Testing Required' according to FDA and is accompanied by a DPWG PGx guideline, whilst no EMA or CPIC PGx guidance is found for this drug-gene pair. Moreover, discrepancies are observed regarding the type of PGx guidance for CYP2C19-doxepin pair, with 89 individuals from our study cohort requiring a dose prescribing change based on FDA, whilst only 5 individuals have to receive genome-guided treatment adjustment according to CPIC. To our knowledge, this is the first study, in which discrepancies regarding the type of PGx guidance and the number of actionable drug-gene pairs amongst FDA and EMA, as well as CPIC and DPWG, are brought to light with an emphasis on psychiatric disorders.
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http://dx.doi.org/10.1016/j.phrs.2021.105538DOI Listing
May 2021

Results of a nationwide survey of Japanese pharmacists regarding the application of pharmacogenomic testing in precision medicine.

J Clin Pharm Ther 2021 Jun 8;46(3):649-657. Epub 2021 Feb 8.

Department of Pharmacy, Shiga University of Medical Science Hospital, Otsu City, Shiga, Japan.

What Is Known And Objective: Pharmacogenomics (PGx) testing can be effective for supporting precision medicine. The purpose of this study was to assess the knowledge, attitude and practice behaviours of pharmacists in relation to such testing through a survey. We also aimed to identify potential obstacles to implementation of PGx testing by pharmacists and the characteristics of hospital pharmacists involved.

Methods: We performed a web-based survey regarding PGx in Japan. The survey contained a questionnaire related to PGx, which consisted of 30 items and was made accessible via the official Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS) website. The characteristics of hospital pharmacists associated with involvement in PGx testing were evaluated using univariate and multivariate analyses.

Results And Discussion: One thousand three-hundred and thirteen pharmacists responded to the survey. The results revealed that the majority of respondents recognized the role that germline PGx testing can play in determining individual drug responses and that pharmacists have embraced the potential of PGx testing to improve patient care. However, only 26% of pharmacists were involved in PGx testing. We also found that most respondents (81.0%) believed that the lack of insurance coverage for PGx testing was a major barrier to its clinical implementation. Hospital pharmacists involved in PGx testing included certified pharmacists in JSPHCS and pharmacists who had studied PGx in university; however, only 12.4% of pharmacists had received specific PGx-related education.

What Is New And Conclusion: The findings of this survey highlight the necessity to increase the number of PGx tests covered by insurance, and the importance of effective education to inform and facilitate clinical implementation of PGx testing.
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http://dx.doi.org/10.1111/jcpt.13367DOI Listing
June 2021

Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm).

Hum Genome Var 2021 Feb 4;8(1). Epub 2021 Feb 4.

University of Patras, School of Health Sciences, Department of Pharmacy, Laboratory of Pharmacogenomics and Individualised Therapy, Patras, Greece.

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.
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http://dx.doi.org/10.1038/s41439-021-00135-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862625PMC
February 2021

Update on next generation sequencing of pharmacokinetics-related genes: Development of the PKseq panel, a platform for amplicon sequencing of drug-metabolizing enzyme and drug transporter genes.

Drug Metab Pharmacokinet 2021 Apr 26;37:100370. Epub 2020 Nov 26.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address:

Genetic variation in pharmacokinetics (PK)-related genes encoding drug metabolizing enzymes or drug transporters is one of the most practical pharmacogenetic biomarkers for the prediction or explanation of an individual's response to drugs. Many pharmacogenomic variations are identified using targeted, whole-exome, and whole-genome sequencing, and the number of known novel variations and alleles in PK-related genes is increasing. The high homology of sequences among PK-related genes is suspected to lead to potential read misalignment and genotyping errors when short-read sequencing was performed. Therefore, highly efficient and accurate next generation sequencing (NGS) platforms for the sequencing of PK-related genes are needed. We have developed PKseq, a targeted sequencing panel based on multiplex PCR, which targets the coding regions of 37 drug transporters, 30 cytochrome P450 isoforms, 10 UDP-glucuronosyltransferases, 5 flavin-containing monooxygenases, 4 glutathione S-transferases, 4 sulfotransferases, and 10 other genes. In this review, we describe the current NGS platforms for the sequencing of PK-related genes. The NGS platforms, including the PKseq panel, will be useful not only for the identification of all the variants of PK-related genes associated with adverse drug reactions and drug efficacy, but also for clinical sequencing to achieve pharmacogenomics-based stratified medicine.
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http://dx.doi.org/10.1016/j.dmpk.2020.11.005DOI Listing
April 2021

Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations.

Clin Pharmacol Ther 2021 Oct 1;110(4):975-985. Epub 2021 Jan 1.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.

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 nonsmokers, former smokers, 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 (EUR)-ancestry populations 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.
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http://dx.doi.org/10.1002/cpt.2135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187466PMC
October 2021

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations.

Sci Rep 2020 12 4;10(1):21310. Epub 2020 Dec 4.

Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates.

Genetic variations have an established impact on the pharmacological response. Investigating this variation resulted in a compilation of variants in "pharmacogenes". The emergence of next-generation sequencing facilitated large-scale pharmacogenomic studies and exhibited the extensive variability of pharmacogenes. Some rare and population-specific variants proved to be actionable, suggesting the significance of population pharmacogenomic research. A profound gap exists in the knowledge of pharmacogenomic variants enriched in some populations, including the United Arab Emirates (UAE). The current study aims to explore the landscape of variations in relevant pharmacogenes among healthy Emiratis. Through the resequencing of 100 pharmacogenes for 100 healthy Emiratis, we identified 1243 variants, of which 63% are rare (minor allele frequency ≤ 0.01), and 30% were unique. Filtering the variants according to Pharmacogenomics Knowledge Base (PharmGKB) annotations identified 27 diplotypes and 26 variants with an evident clinical relevance. Comparison with global data illustrated a significant deviation of allele frequencies in the UAE population. Understudied populations display a distinct allelic architecture and various rare and unique variants. We underscored pharmacogenes with the highest variation frequencies and provided investigators with a list of candidate genes for future studies. Population pharmacogenomic studies are imperative during the pursuit of global pharmacogenomics implementation.
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http://dx.doi.org/10.1038/s41598-020-78231-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718919PMC
December 2020

Individual variation in unfractionated heparin dosing after pediatric cardiac surgery.

Sci Rep 2020 11 10;10(1):19438. Epub 2020 Nov 10.

Division of Critical Care Medicine, Department of Critical Care and Anesthesia, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

We aimed to identify attributing factors to the interindividual variabilities of the infusion rates in unfractionated heparin therapy. We included patients who required unfractionated heparin therapy to achieve the target APTT after cardiac surgery between May 2014 and February 2018. Fifty-nine patients were included, of whom 8 underwent Blalock-Taussig shunt; 27, Glenn procedure; 19, Fontan procedure; 3, mechanical valve replacement; and 2, Rastelli procedure. Previously reported variables that influenced the response to unfractionated heparin treatment were initially compared, which included age; weight; sex; type of surgery; platelet count; fibrinogen, antithrombin III, total protein, albumin, alanine transaminase, and creatinine levels; and use of fresh frozen plasma. The type of surgical procedure was found to be significantly associated with the differences in heparin infusion rate (P = 0.00073). Subsequently, the variance explained by these factors was estimated through a selection based on the minimum Akaike information criterion value; models constructed by various combinations of the surgery types were compared. The model including the Blalock-Taussig shunt, Glenn procedure, and mechanical valve replacement showed the highest summed variance explained (29.1%). More than 70% of the interindividual variability in initial heparin maintenance dosing was unexplained.
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http://dx.doi.org/10.1038/s41598-020-76547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655810PMC
November 2020

A meta-analysis of the influence of ADRB2 genetic polymorphisms on albuterol (salbutamol) therapy in patients with asthma.

Br J Clin Pharmacol 2021 04 25;87(4):1708-1716. Epub 2020 Oct 25.

Department of Management and Strategy, Clinical Research Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.

Aims: The associations of 2 nonsynonymous single nucleotide polymorphisms (Arg16Gly and Gln27Glu) in the adrenoceptor β2 (ADRB2) gene with response after albuterol use are conflicting. We conducted a meta-analysis to examine the cumulative evidence of the effects of these 2 variants on percent forced expiratory volume in 1 second (FEV1.0%) after albuterol use in asthma patients.

Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify studies examining the association between ADRB2 Arg16Gly and Gln27Glu and FEV1.0% shortly after albuterol administration. The individual study results were combined with weights based on the inverse variance method. This systematic review was registered in the PROSPERO (registration number: CRD42019074554).

Results: Among 273 initial studies identified, 7 studies met the inclusion criteria for quantitative evaluation. Results of the overall meta-analysis indicated no statistically significant mean difference of FEV1.0% between genotypes of Arg16Gly and Gln27Glu. In subgroup analyses, significant associations were found for Arg16Gly GG (vs AA) among studies where no methacholine bronchoconstriction was conducted (mean difference, -3.92; 95% confidence interval, -7.29 to -0.54; I = 0%), and for Arg16Gly GG (vs GA) among studies that included patients with no comorbidities (mean difference, -1.93; 95% confidence interval, -3.77 to -0.10; I = 0%).

Conclusion: Synthesis of the studies to date shows weak evidence for an association between ADRB2 Arg16Gly and Gln27Glu and FEV1.0% after albuterol use, results of which underscore significant heterogeneity across studies and the need for careful design and sample size considerations.
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http://dx.doi.org/10.1111/bcp.14570DOI Listing
April 2021

Editorial: Big Data, Pharmacogenomics and Real-World Research in Pharmacology.

Front Pharmacol 2020 13;11:1239. Epub 2020 Aug 13.

RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.

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http://dx.doi.org/10.3389/fphar.2020.01239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438593PMC
August 2020

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

J Hum Genet 2021 Feb 5;66(2):139-149. Epub 2020 Aug 5.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. K, V, and intrinsic clearance (V/K) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the V/K value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.
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http://dx.doi.org/10.1038/s10038-020-0815-xDOI Listing
February 2021

Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

Clin Pharmacol Ther 2020 09 2;108(3):625-634. Epub 2020 Aug 2.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR ; e.g., rs74497159, β per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), β per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); P  = 3.62 × 10 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.
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http://dx.doi.org/10.1002/cpt.1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718413PMC
September 2020

Evaluation of gefitinib systemic exposure in EGFR-mutated non-small cell lung cancer patients with gefitinib-induced severe hepatotoxicity.

Cancer Chemother Pharmacol 2020 03 10;85(3):605-614. Epub 2020 Feb 10.

Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: Severe hepatotoxicity induced by the standard dose of gefitinib (250 mg daily) often becomes manageable by dose reduction to 250 mg every other day. Thus, we hypothesized that systemic exposure of standard-dose gefitinib in patients with experience of severe hepatotoxicity might be higher than that in patients without severe hepatotoxicity.

Methods: Patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer who were receiving gefitinib either at a reduced dose (250 mg every other day) because of intolerable severe toxicity or at a standard dose (250 mg daily) were enrolled. A series of blood samples were collected to estimate pharmacokinetic parameters and calculate systemic exposure of standard-dose gefitinib (area under the concentration-time curve from 0 to 24 h at steady state, AUC). Systemic exposure of unbound gefitinib (fu·AUC) was also assessed, because gefitinib is extensively bound to serum proteins.

Results: Of the 38 enrolled patients, 34 (23 patients without experience of severe hepatotoxicity, 11 patients with experience of severe hepatotoxicity) were evaluable. There was no significant differences in total AUC or unbound fu·AUC between patients with and without experience of severe hepatotoxicity. Analysis of the time to severe hepatotoxicity indicated no difference between patients with a high AUC and those with a low AUC of either total or unbound gefitinib.

Conclusion: This study suggests that reversible severe hepatotoxicity is not caused by high systemic exposure of gefitinib.
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http://dx.doi.org/10.1007/s00280-020-04034-yDOI Listing
March 2020

Human leukocyte antigen DRB1*04:05 and clozapine-induced agranulocytosis/granulocytopenia.

Aust N Z J Psychiatry 2020 05 22;54(5):545-546. Epub 2020 Jan 22.

Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Japan.

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http://dx.doi.org/10.1177/0004867419900296DOI Listing
May 2020

Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study.

J Clin Oncol 2020 02 10;38(6):558-566. Epub 2019 Dec 10.

Keio University School of Medicine, Tokyo, Japan.

Purpose: In patients taking tamoxifen, the genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome.

Methods: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes.

Results: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM 51.1 nM; < .0001) and were also higher compared with wt/wt patients (72.0 nM; = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months ( = .43).

Conclusion: In patients with -variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The genotype solely cannot explain individual variability in the efficacy of tamoxifen.
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http://dx.doi.org/10.1200/JCO.19.01412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030889PMC
February 2020

HLA-B*51:01 and CYP2C9*3 Are Risk Factors for Phenytoin-Induced Eruption in the Japanese Population: Analysis of Data From the Biobank Japan Project.

Clin Pharmacol Ther 2020 05 6;107(5):1170-1178. Epub 2019 Dec 6.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.

CYP2C9*3 and HLA-B alleles are reportedly associated with phenytoin-induced eruption in some East Asian populations; however, this finding is not readily applicable to the Japanese population. Thus, we aimed to investigate the risk alleles using samples and data from BioBank Japan. A total of 747 patients (24 cases and 723 tolerant controls) were selected for analysis. Case-control association studies were conducted, using CYP2C9*3, CYP2C9*27, CYP2C19*2, CYP2C19*3, and HLA-B allele genotype data. CYP2C9*3 carrier status was significantly associated with phenytoin-induced eruption (P = 0.0022, odds ratio 7.05, 95% confidence interval, 2.44-20.4). HLA-B*51:01 showed the most prominent association (P = 0.010, odds ratio 3.19, 95% confidence interval, 1.37-7.48). Including both of these features improved predictive performance, measured as area under the receiver operating characteristic curve, by 10%. CYP2C9*3 and HLA-B*51:01 allele carrier statuses are significantly associated with phenytoin-induced eruption; thus, checking this carrier status before prescription would decrease the incidence of phenytoin-induced eruption in clinical practice.
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http://dx.doi.org/10.1002/cpt.1706DOI Listing
May 2020

A Genome-Wide Association Study Identifies Five Novel Genetic Markers for Trastuzumab-Induced Cardiotoxicity in Japanese Population.

Biol Pharm Bull 2019 Dec 9;42(12):2045-2053. Epub 2019 Oct 9.

Project for Development of Liquid Biopsy Diagnosis, Japanese Foundation for Cancer Research, Research Institute.

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10 - 2.01 × 10) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, P = 6.00 × 10, 8.88 × 10, 1.07 × 10, 1.42 × 10, 1.60 × 10, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.
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http://dx.doi.org/10.1248/bpb.b19-00527DOI Listing
December 2019

Comparison of effects of UGT1A1*6 and UGT1A1*28 on irinotecan-induced adverse reactions in the Japanese population: analysis of the Biobank Japan Project.

J Hum Genet 2019 Dec 4;64(12):1195-1202. Epub 2019 Oct 4.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.

It has been reported that there are differences in effects on irinotecan-induced adverse reactions between UGT1A1*6 and UGT1A1*28. In order to compare those differences in the Japanese population, we examined the associations between UGT1A1 and irinotecan-induced adverse reactions using the BioBank Japan Project database. We genotyped UTG1A1*6 and UGT1A1*28 and conducted case-control analyses. A total of 651 patients (102 cases and 549 tolerant controls) were included in this study. The results showed that UGT1A1*6/*6 is a predictor of adverse drug reactions (ADRs) (p-value 0.00070, odds ratio 6.59, 95% confidence interval 2.33-18.6), whereas UGT1A1*6/*28 and UGT1A1*28/*28 were not. The subanalysis comprising only patients with UGT1A1*6/*6, UGT1A1*6/*28, and UGT1A1*28/*28 revealed a trend towards an increased risk of ADRs in patients with UGT1A1*6 (p-value 0.0092, odds ratio 4.39, 95% confidence interval 1.57-14.9). Multiple logistic regression analyses showed that use of platinum-based antineoplastic drugs and presence of UGT1A1*6/*6 were independent variables, significantly associated with ADRs. The diagnostic performance of a predictive model had a sensitivity of 49.0%, specificity of 70.1%, and a number needed to screen of 5.8. We concluded that UGT1A1 testing could be useful to predict irinotecan-induced ADRs, and that UTG1A1*6 rather than UGT1A1*28 contributed to ADR occurrence.
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http://dx.doi.org/10.1038/s10038-019-0677-2DOI Listing
December 2019

The Influence of Beta-2 Adrenergic Receptor Gene Polymorphisms on Albuterol Therapy for Patients With Asthma: Protocol for a Systematic Review and Meta-Analysis.

JMIR Res Protoc 2019 Sep 16;8(9):e14759. Epub 2019 Sep 16.

Department of Management and Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan.

Background: Albuterol is one of the most frequently used medications in clinical practice and seeing varying responses to albuterol between individuals is not uncommon. Multiple studies have been conducted to investigate the associations of differing responses due to albuterol, particularly with regards to the two nonsynonymous single nucleotide polymorphisms (SNPs) at positions 16 (Arg16Gly: substitution of arginine to glycine at position 16; rs1042713) and 27 (Glu27Gln: substitution of glutamic acid to glutamine at position 27; rs1042714) on the β-2 adrenergic receptor (ADRB2) gene. However, the directions of the correlations are conflicting.

Objective: The objective of this systematic review and meta-analysis is to assess the effect of the two SNPs on the ADRB2 gene, in terms of the responses that present in asthmatic patients shortly after albuterol inhalation.

Methods: The primary outcome of this work is a detailed study of the associations of the two SNPs in the ADRB2 gene with treatment response and lung function testing shortly after administration of albuterol to asthmatic patients. A comprehensive literature search, using the OVID platform, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, will be conducted by a specialized librarian without language restrictions. We will include both prospective and retrospective original observational studies, and we will exclude nonhuman or in vitro studies. All abstracts will be reviewed by two authors who will also individually perform data extraction from each eligible study. Any arising disagreements will be resolved through discussion with a third party. Risk of bias for all included studies will be independently assessed using the quality of genetic association studies tool. We will report the systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A narrative synthesis of study results or meta-analyses will be undertaken when appropriate.

Results: At the moment of writing, we have already started the preliminary literature search and piloting of the study selection process. The anticipated completion date is September 30, 2019.

Conclusions: Our systematic review and meta-analysis aims to clarify the current evidence of associations between the two nonsynonymous SNPs in the ADRB2 gene and the responses that present in asthmatic patients shortly after albuterol inhalation. If positive correlations are found, this knowledge may be used to improve personalized pharmacotherapy of albuterol use.

Trial Registration: PROSPERO CRD42019074554; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=74554.

International Registered Report Identifier (irrid): PRR1-10.2196/14759.
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http://dx.doi.org/10.2196/14759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773362PMC
September 2019

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Clin Cancer Res 2019 10 11;25(19):5913-5924. Epub 2019 Jul 11.

Department of Medicine, University of Chicago, Chicago, Illinois.

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels.

Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model.

Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted = 2.13 × 10). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted = 6.58 × 10). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR = 1.46; = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR = 1.68, = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 ( = 4.6 × 10, a SNP intronic to ).

Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774840PMC
October 2019

Genomewide Association Study Confirming the Association of with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai Patients.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Antituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly 1 million single-nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the -acetyltransferase () region. The A allele of rs1495741, the top SNP in the intergenic region of and (14 kb from ), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57];  = 6.86E-11). This particular SNP was reported as a tag SNP for inferred phenotypes. The AA, AG, and GG genotypes represented slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with acetylator phenotypes. This GWAS shows that is the most important risk factor for ATDILI in the Thai population.
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http://dx.doi.org/10.1128/AAC.02692-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658740PMC
August 2019
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