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

Eur J Clin Pharmacol. 2021 Jan 29;:

Authors: Wang T, Zhou Y, Cao G

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

PMID: 33515076 [PubMed - as supplied by publisher]

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

Front Pharmacol. 2020;11:614048

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

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

PMID: 33510640 [PubMed]

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

Front Pharmacol. 2020;11:551522

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

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

PMID: 33510634 [PubMed]

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

Psychiatry Res. 2020 Nov 15;297:113571

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

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

PMID: 33513485 [PubMed - as supplied by publisher]

A Placebogenomics/Nocebogenomics Challenge to Pharmacogenomics, Nutrigenomics, and Vaccinomics: Why Should We Rethink Association Study Designs?

OMICS. 2021 Jan 29;:

Authors: Özdemir V

PMID: 33513040 [PubMed - as supplied by publisher]

Precision Dosing for Tacrolimus Using Genotypes and Clinical Factors in Kidney Transplant Recipients of European Ancestry.

J Clin Pharmacol. 2021 Jan 29;:

Authors: Al-Kofahi M, Oetting WS, Schladt DP, Remmel RP, Guan W, Wu B, Dorr CR, Mannon RB, Matas AJ, Israni AK, Jacobson PA

Abstract
Genetic variation. This article is protected by copyright. All rights reserved.

PMID: 33512723 [PubMed - as supplied by publisher]

No Impact of Soluble Epoxide Hydrolase rs4149243, rs2234914 and rs751142 Genetic Variants on the Development of Type II Diabetes and its Hypertensive Complication among Jordanian Patients.

Int J Clin Pract. 2021 Jan 29;:e14036

Authors: Khamees M, Jarrar Y, Al-Qirim T, Mahmoud IS, Hatmal MM, Alshaer W, Lee SJ

Abstract
BACKGROUND: Human soluble epoxide hydrolase plays a major role in cardiovascular homeostasis. Genetic variants in the EPHX2 gene among different ethnic groups are associated with cardiovascular complications, such as hypertension. However, no reports regarding the association of EPHX2 genotype with hypertension among type II diabetic (T2D) patients of Middle Eastern Jordanian origin exist.
OBJECTIVE: The current study aimed to elucidate the association of the EPHX2 allele, genotype, and haplotype with T2D, hypertension, and parameters of lipid profile parameters among Jordanian T2D patients.
METHODS: Ninety-three genomic DNA samples of non-diabetic controls and 97 samples from T2D patients were genotyped for EPHX2 rs4149243, rs2234914, and rs751142 genetic variants. The DNA samples were amplified using polymerase chain reaction (PCR) and then sequenced using Applied Biosystems Model (ABI3730x1). The functionality of intronic EPHX2 variants was predicted using the in silico Berkely Drosophila Genome Project software.
RESULTS: We found no significant (P > 0.05) association between the EPHX2 rs4149243, rs2234914, and rs751142 allele, genotype, and haplotype and the incidence of T2D and hypertension. Additionally, no association (P > 0.05) between these EPHX2 genetic variants with the baseline total cholesterol, low- and high-density lipoproteins, and triglycerides among both non-diabetic and diabetic volunteers was found. However, we found an inter-ethnic variation (χ2 -test, p value ˂ 0.05) in the allele frequency of the EPHX2 rs4149243 and rs2234914 variants between Jordanians and other ethnic populations. Also, the in silico Berkely Drosophila Genome Project software predicted that the intronic EPHX2 rs4149243 could alter the splicing of intron 7.
CONCLUSIONS: It can be concluded from this study that EPHX2 rs4149243, rs2234914, and rs751142 genetic variants do not play a role in the development of T2D and hypertension among Jordanian T2D patients. Further genetic studies with larger sample sizes are needed to find out the association of other functional EPHX2 variants with cardiovascular diseases among T2D patients in Jordan.

PMID: 33512081 [PubMed - as supplied by publisher]

Fas-Associated Factor 1 Promotes Hepatic Insulin Resistance via JNK Signaling Pathway.

Oxid Med Cell Longev. 2021;2021:3756925

Authors: Sun B, Zhou J, Gao Y, He F, Xu H, Chen X, Zhang W, Chen L

Abstract
Fas-associated factor 1 (FAF1), a member of the Fas death-inducing signaling complex, is reported to interact potentially with diverse proteins and function in diverse cellular possesses. It remains unclear, however, whether FAF1 is involved in hepatic metabolic disorder and insulin resistance. This study is aimed at elucidating the role and the molecular mechanism of FAF1 in hepatic insulin resistance. Rats treated with high-fat diets are used as hepatic insulin resistance animal models. Quantitative real-time PCR, immunohistochemistry, and immunofluorescence assay are utilized to detect the FAF1 expression. The expression of relevant proteins is detected by Western blotting. We determine ROS production, lipid accumulation, and glucose uptake by using flow cytometry. Immunoprecipitation is employed to investigate protein-protein interaction. We find that increased expression of FAF1 occurred in the livers of insulin-resistant rats. Using gain-of-function and loss-of-function approaches, we observe dramatic exacerbation of insulin resistance, upregulated gluconeogenesis genes, downregulated glucose transport genes, and enhanced ROS production by FAF1 overexpression, whereas downregulation of FAF1 leads to a completely opposite phenotype. Mechanistically, FAF1 interacts directly with c-Jun N-terminal kinase (JNK) and activates its phosphorylation, thereby blocking the downstream insulin signaling pathway and leading to insulin resistance. Our data indicate that FAF1 is a potent regulator in hepatic metabolic disorder and insulin resistance.

PMID: 33510836 [PubMed - in process]

Lung microbiome mediates the progression from chronic obstructive pulmonary disease to lung cancer through inflammation.

Yi Chuan. 2021 Jan 20;43(1):30-39

Authors: Wang YJ, Wu SS, Chu J, Kong XY

Abstract
Lung microbiome exists in the respiratory tract and parenchymal tissues. It mediates lung injury through a variety of mechanisms, including bacterial disturbance, metabolites, inflammatory response, immune response, and genotoxicity. Accumulating evidences suggest that changes in lung microbiome correlates with chronic obstructive pulmonary disease (COPD) and lung cancer, and the microbiome promotes the progression from COPD to lung cancer. In this review, we mainly introduce the impairment of the homeostasis of the lung microbiome and its inflammation that leads to COPD and lung cancer, then focus on how the microbiome mediates the progression from COPD to lung cancer through inflammatory response. The review may provide a new theoretical basis for clinical prevention, optimal treatment strategy and design of new drugs for COPD and lung cancer.

PMID: 33509772 [PubMed - in process]

Primary Immunodeficiencies: Diseases of Children and Adults - A Review.

Adv Exp Med Biol. 2021;1289:37-54

Authors: Lewandowicz-Uszyńska A, Pasternak G, Świerkot J, Bogunia-Kubik K

Abstract
Primary immunodeficiencies (PIDs) belong to a group of rare congenital diseases occurring all over the world that may be seen in both children and adults. In most cases, genetic predispositions are already known. As shown in this review, genetic abnormalities may be related to dysfunction of the immune system, which manifests itself as recurrent infections, increased risk of cancer, and autoimmune diseases. This article reviews the various forms of PIDs, including their characterization, management strategies, and complications. Novel aspects of the diagnostics and monitoring of PIDs are presented.

PMID: 32803731 [PubMed - indexed for MEDLINE]

A Practical Utility and Benefit of Pharmacogenetic-based Antidepressant Treatment Strategy for Major Depressive Disorder Patients with Difficult-to-treat.

Clin Psychopharmacol Neurosci. 2021 Feb 28;19(1):160-165

Authors: Lee KH, Bahk WM, Lee SJ, Serretti A, Pae CU

Abstract
Objective: We report the results of pharmacogenomics-based antidepressant treatment (PGXt) results in treating treatment-resistant major depressive disorder (TRD) patients in real practice.
Methods: Nine patients were prescribed NeuropharmagenⓇ for selection of antidepressants for individual patient and their clinical outcomes were followed.
Results: After treatment by PGXt results from current antidepressants, substantial reduction of depressive symptoms was observed at some point and maintained during observation period in six patients.
Conclusion: Our case series potentially shows the clinical utility and benefit of PGXt for treatment of TRD patients.

PMID: 33508800 [PubMed - as supplied by publisher]

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. 2020 Nov 26;37:100370

Authors: Fukunaga K, Momozawa Y, Mushiroda T

Abstract
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.

PMID: 33508759 [PubMed - as supplied by publisher]

SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement.

Lancet Gastroenterol Hepatol. 2021 Jan 25;:

Authors: Alexander JL, Moran GW, Gaya DR, Raine T, Hart A, Kennedy NA, Lindsay JO, MacDonald J, Segal JP, Sebastian S, Selinger CP, Parkes M, Smith PJ, Dhar A, Subramanian S, Arasaradnam R, Lamb CA, Ahmad T, Lees CW, Dobson L, Wakeman R, Iqbal TH, Arnott I, Powell N, Inflammatory Bowel Disease section of the British Society of Gastroenterology and the the Inflammatory Bowel Disease Clinical Research Group

Abstract
SARS-CoV-2 has caused a global health crisis and mass vaccination programmes provide the best opportunity for controlling transmission and protecting populations. Despite the impressive clinical trial results of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines, important unanswered questions remain, especially in patients with pre-existing conditions. In this position statement endorsed by the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) section and IBD Clinical Research Group, we consider SARS-CoV-2 vaccination strategy in patients with IBD. The risks of SARS-CoV-2 vaccination are anticipated to be very low, and we strongly support SARS-CoV-2 vaccination in patients with IBD. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV-2 vaccination may be diminished in some patients with IBD, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in patients treated with anti-TNF drugs, are likely to outweigh these theoretical concerns. Key areas for further research are discussed, including vaccine hesitancy and its effect in the IBD community, the effect of immunosuppression on vaccine efficacy, and the search for predictive biomarkers of vaccine success.

PMID: 33508241 [PubMed - as supplied by publisher]

Impact and applicability of pharmacogenomics in rheumatology: an integrated analysis.

Clin Exp Rheumatol. 2021 Jan 15;

Authors: Reid P, Danahey K, Lopez Velazquez M, Ratain MJ, O'Donnell PH

Abstract
OBJECTIVES: Rheumatology medications are often associated with adverse drug reactions (ADRs) or inadequate response (IR). Pharmacogenomics may be a solution, but there is limited knowledge of its potential utility within rheumatology.
METHODS: We analysed medication changes and pharmacogenomically actionable prescriptions for all adult rheumatology outpatient encounters at our medical centre between 10/2012-12/2018. Three sources defined pharmacogenomic actionability: FDA labels, Clinical Pharmacogenetics Implementation Consortium guidelines, and our institutionally-deliverable pharmacogenomic clinical decision support (CDS) summaries. A subset of patients (validation cohort) had previously undergone broad, preemptive pharmacogenomic testing within other clinics but results were unavailable within rheumatology. We assessed the occurrence of specific pharmacogenomic ADRs/IRs in this group.
RESULTS: From 174,834 prescribing events, 6300/7761 patients (81%) had clinically actionable pharmacogenomic drug prescriptions (i.e. institutional CDS summaries would have been deployable if testing had been done). Using more conservative standards (pharmacogenomically actionable by ≥2 guidance bodies), 4158/7761 (54%) patient prescriptions could have been impacted. The greatest proportions of potentially impacted rheumatologic prescriptions were for tramadol (47%), allopurinol (21%), azathioprine (17%) and celecoxib (8%). Among our validation cohort (94 previously-genotyped patients), 29 (31%) patients had a pharmacogenomic genotype that would have cautioned possible ADRs/IRs for ≥1 medication. Four patients actually suffered ADRs/IRs that would have been predicted by preemptive genotyping.
CONCLUSIONS: Pharmacogenomic genotyping could inform prescribing for the majority of rheumatology patients and may prevent a subset of ADRs/IRs. These findings justify prospective evaluation of pharmacogenomic testing including assessment of cost-effectiveness in selected rheumatology populations to further understand impact on therapy-related toxicities and treatment outcomes.

PMID: 33506753 [PubMed - as supplied by publisher]

Insight on the Genetics of Atrial Fibrillation in Puerto Rican Hispanics.

Stroke Res Treat. 2021;2021:8819896

Authors: Gonzalez-Cordero AF, Duconge-Soler J, Franqui-Rivera H, Feliu-Maldonado R, Roche-Lima A, Almodovar-Rivera I

Abstract
Non-Hispanic whites present with higher atrial fibrillation (AF) prevalence than other racial minorities living in the mainland USA. In two hospital-based studies, Puerto Rican Hispanics had a lower prevalence of atrial fibrillation of 2.5% than non-Hispanic Whites with 5.7%. This data is particularly controversial because Hispanics possess a higher prevalence of traditional risk factors for developing AF yet have a lower AF prevalence. This phenomenon is known as the atrial fibrillation paradox. Despite recent advancements in understanding AF, its pathogenesis remains unclear. In this study, we compared a genetic dataset of Puerto Rican Hispanics to 111 SNP known to be associated with AF in a large European cohort and determine if they are associated with AF susceptibility in our cohort. To achieve this aim, we performed a secondary analysis of existing data using the following two studies: (1) The Pharmacogenetics of Warfarin in Puerto Ricans study and the (2) A Genomic Approach for Clopidogrel in Caribbean Hispanics, and assess for the presence of European SNPs associated with AF from the genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation. We used data from 555 cardiovascular Puerto Rican Hispanic patients, consisting of 486 control and 69 cases. We found that the following SNPs showed significant association with AF in PHR: rs2834618, rs6462079, rs7508, rs2040862, and rs10458660. Some of these SNPs are proteins involved in lysosomal activities responsible for breaking ceramides to sphingosines and collagen deposition around atrial cardiomyocytes. Furthermore, we performed a machine learning analysis and determined that Native American admixture and heart failure were strongly predictive of AF in PHR. For the first time, this study provides some genetic insight into AF's mechanisms in a Puerto Rican Hispanic cohort.

PMID: 33505650 [PubMed]

EGFR Mutation Analysis in Non-small Cell Lung Carcinoma Patients: A Liquid Biopsy Approach.

Indian J Clin Biochem. 2021 Jan;36(1):51-58

Authors: Joshi J, Raval A, Desai U, Upadhyay V, Bhavsar M, Shah K, Rawal R, Panchal H, Shah F

Abstract
In the era of the targeted therapy identification of EGFR mutation detection in lung cancer is extremely helpful to predict the treatment efficacy of EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, the inadequacy and quality of the biopsy samples are the major obstacles in molecular testing of EGFR mutation in lung cancer. To address this issue, the present study intended to use liquid biopsy as the non-invasive method for EGFR mutation detection. A total of 31 patients with an advanced stage of lung cancer were enrolled in the study from which cell-free DNA (cfDNA) and FFPE tissue DNA was extracted. Extracted DNA samples were analyzed for further EGFR exon specific mutation analysis by ARMS-PCR. Data were analyzed statistically using SPSS software. In cfDNA samples, the prevalence of wild type EGFR was 48% while the prevalence of TKI resistant and TKI sensitive mutations were 3%. Conversely, in tissue DNA samples, the prevalence of wild type, TKI sensitive and TKI resistant mutations were 48%, 19%, and 3%, respectively. The overall concordance of EGFR mutation between cfDNA and tissue DNA was 83%. McNemar's test revealed that there was no significant difference between EGFR expression of cfDNA and tissue DNA samples. Additionally, the significant-high incidence of TKI resistant mutations was observed in tobacco habituates, indicating the role of carcinogens present in the tobacco in developing resistant mutations. In conclusion, our data suggest that evaluation of EGFR mutation from cfDNA samples is practicable as a non-invasive tool in patients with advanced-stage of lung cancer.

PMID: 33505127 [PubMed]

The Human Phenotype Ontology in 2021.

Nucleic Acids Res. 2021 01 08;49(D1):D1207-D1217

Authors: Köhler S, Gargano M, Matentzoglu N, Carmody LC, Lewis-Smith D, Vasilevsky NA, Danis D, Balagura G, Baynam G, Brower AM, Callahan TJ, Chute CG, Est JL, Galer PD, Ganesan S, Griese M, Haimel M, Pazmandi J, Hanauer M, Harris NL, Hartnett MJ, Hastreiter M, Hauck F, He Y, Jeske T, Kearney H, Kindle G, Klein C, Knoflach K, Krause R, Lagorce D, McMurry JA, Miller JA, Munoz-Torres MC, Peters RL, Rapp CK, Rath AM, Rind SA, Rosenberg AZ, Segal MM, Seidel MG, Smedley D, Talmy T, Thomas Y, Wiafe SA, Xian J, Yüksel Z, Helbig I, Mungall CJ, Haendel MA, Robinson PN

Abstract
The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

PMID: 33264411 [PubMed - indexed for MEDLINE]

HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine.

Nucleic Acids Res. 2021 01 08;49(D1):D1197-D1206

Authors: Fang S, Dong L, Liu L, Guo J, Zhao L, Zhang J, Bu D, Liu X, Huo P, Cao W, Dong Q, Wu J, Zeng X, Wu Y, Zhao Y

Abstract
Pharmacotranscriptomics has become a powerful approach for evaluating the therapeutic efficacy of drugs and discovering new drug targets. Recently, studies of traditional Chinese medicine (TCM) have increasingly turned to high-throughput transcriptomic screens for molecular effects of herbs/ingredients. And numerous studies have examined gene targets for herbs/ingredients, and link herbs/ingredients to various modern diseases. However, there is currently no systematic database organizing these data for TCM. Therefore, we built HERB, a high-throughput experiment- and reference-guided database of TCM, with its Chinese name as BenCaoZuJian. We re-analyzed 6164 gene expression profiles from 1037 high-throughput experiments evaluating TCM herbs/ingredients, and generated connections between TCM herbs/ingredients and 2837 modern drugs by mapping the comprehensive pharmacotranscriptomics dataset in HERB to CMap, the largest such dataset for modern drugs. Moreover, we manually curated 1241 gene targets and 494 modern diseases for 473 herbs/ingredients from 1966 references published recently, and cross-referenced this novel information to databases containing such data for drugs. Together with database mining and statistical inference, we linked 12 933 targets and 28 212 diseases to 7263 herbs and 49 258 ingredients and provided six pairwise relationships among them in HERB. In summary, HERB will intensively support the modernization of TCM and guide rational modern drug discovery efforts. And it is accessible through http://herb.ac.cn/.

PMID: 33264402 [PubMed - indexed for MEDLINE]

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

Clin Transl Sci. 2021 Jan 27;:

Authors: Fohner AE, Dalton R, Skagen K, Jackson K, Claw KG, Hopkins SE, Robinson R, Khan BA, Prasad B, Schuetz EG, Nickerson DA, Thornton TA, Dillard DA, Boyer BB, Thummel KE, Woodahl EL

Abstract
The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4β-vitamin D hydroxylation activity in Yup'ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele-coupled with low frequency of the functional CYP3A5*1 variant-may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.

PMID: 33503331 [PubMed - as supplied by publisher]

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.

Inflamm Bowel Dis. 2021 Jan 27;:

Authors: Suzuki K, Kakuta Y, Naito T, Takagawa T, Hanai H, Araki H, Sasaki Y, Sakuraba H, Sasaki M, Hisamatsu T, Motoya S, Matsumoto T, Onodera M, Ishiguro Y, Nakase H, Andoh A, Hiraoka S, Shinozaki M, Fujii T, Katsurada T, Kobayashi T, Fujiya M, Otsuka T, Oshima N, Suzuki Y, Sato Y, Hokari R, Noguchi M, Ohta Y, Matsuura M, Kawai Y, Tokunaga K, Nagasaki M, Kudo H, Minegishi N, Okamoto D, Shimoyama Y, Moroi R, Kuroha M, Shiga H, Li D, McGovern DPB, Kinouchi Y, Masamune A, MENDEL study group

Abstract
BACKGROUND: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD.
METHODS: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance.
RESULTS: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%).
CONCLUSIONS: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

PMID: 33501934 [PubMed - as supplied by publisher]