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Clinical Genetics Mar 2018For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the... (Review)
Review
For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug-related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.
Topics: Alleles; Autoimmune Diseases; Disease Management; Drug Discovery; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Molecular Targeted Therapy; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precision Medicine
PubMed: 29194620
DOI: 10.1111/cge.13186 -
Pharmacotherapy Sep 2017Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as... (Review)
Review
Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing.
Topics: Anticoagulants; Ethnicity; Humans; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Warfarin
PubMed: 28672100
DOI: 10.1002/phar.1982 -
Clinical Pharmacology and Therapeutics Apr 2020Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidence make it difficult to consolidate and... (Review)
Review
Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidence make it difficult to consolidate and link them to clinical consequences. Consequently, we developed information retrieval (IR) models to retrieve DDI and drug-gene interaction (DGI) evidence from 25 million PubMed abstracts and distinguish DDI evidence into in vitro pharmacokinetic (PK), clinical PK, and clinical pharmacodynamic (PD) studies for US Food and Drug Administration (FDA) approved and withdrawn drugs. Additionally, information extraction models were developed to extract DDI-pairs and DGI-pairs from the IR-retrieved abstracts. An overlapping analysis identified 986 unique DDI-pairs between all 3 types of evidence. Another 2,157 and 13,012 DDI-pairs and 3,173 DGI-pairs were identified from known clinical PK/PD DDI, clinical PD DDI, and DGI evidence, respectively. By integrating DDI and DGI evidence, we discovered 119 and 18 new pharmacogenetic hypotheses associated with CYP3A and CYP2D6, respectively. Some of these DGI evidence can also aid us in understanding DDI mechanisms.
Topics: Data Mining; Drug Interactions; Humans; Knowledge Discovery; Pharmacogenetics; Translational Research, Biomedical; United States; United States Food and Drug Administration
PubMed: 31863452
DOI: 10.1002/cpt.1745 -
The Pharmacogenomics Journal Jan 2018Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external... (Review)
Review
Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients.
Topics: Animals; Biomarkers; Crohn Disease; Genetic Predisposition to Disease; Humans; Pharmacogenetics; Polymorphism, Genetic
PubMed: 28631723
DOI: 10.1038/tpj.2017.27 -
Clinical Genetics Mar 2018In essence, pharmacogenetic research is aimed at discovering variants of importance to gene-treatment interaction. However, epidemiological studies are rarely set up... (Review)
Review
In essence, pharmacogenetic research is aimed at discovering variants of importance to gene-treatment interaction. However, epidemiological studies are rarely set up with this goal in mind. It is therefore of great importance that researchers clearly communicate which assumptions they have had to make, and which inherent limitations apply to the interpretation of their results. This review discusses considerations of, and the underlying assumptions for, utilizing different response phenotypes and study designs popular in pharmacogenetic research to infer gene-treatment interaction effects, with a special focus on those dealing with of clinical effects of drug treatment.
Topics: Clinical Trials as Topic; Disease Susceptibility; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Precision Medicine; Research; Research Design
PubMed: 29136278
DOI: 10.1111/cge.13178 -
The Journal of Allergy and Clinical... Oct 2016Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which... (Review)
Review
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively. Numerous pharmacogenetic associations have been discovered for immediate hypersensitivity reactions to β-lactams, aspirin, and nonsteroidal anti-inflammatory drugs; however, the clinical utility of testing for these genetic associations has not been established. In contrast, pharmacogenetic testing for HLA-B*1502 before carbamazepine in patients of certain Asian ethnicities and testing for HLA-B*5701 before abacavir treatment are recommended. This review will focus on pharmacogenetics and pharmacogenomics and their role in reducing ADRs, especially those caused by drug hypersensitivity reactions.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Risk Factors
PubMed: 27720019
DOI: 10.1016/j.jaci.2016.08.002 -
Current Opinion in Pharmacology Apr 2016Warfarin and other oral vitamin K antagonists (VKAs) have been the primary pharmacologic options with well-established efficacy data in high-risk patient populations.... (Review)
Review
Warfarin and other oral vitamin K antagonists (VKAs) have been the primary pharmacologic options with well-established efficacy data in high-risk patient populations. Warfarin dose requirements to achieve therapeutic anticoagulation are highly variable. This variability in response results in increased risk for adverse events, including thromboembolism and bleeding. Genetic variants in CYP2C9 and VKORC1 have been identified and shown to explain some of the variability in warfarin response. Prospective trials suggest that incorporation of genotype results in faster time to therapeutic range than without; however, whether these improvements result in improved clinical outcomes is unclear. The target-specific anticoagulants are alternatives to warfarin and do not require laboratory monitoring. Some pharmacogenetic variation in their clinical response may exist as well. Ongoing trials will provide a clearer picture of whether genotype-based warfarin dosing improves outcomes and may, therefore, subsequently be compared with the target-specific agents.
Topics: Administration, Oral; Anticoagulants; Fibrinolytic Agents; Genotype; Humans; Pharmacogenetics; Polymorphism, Genetic; Warfarin
PubMed: 26878737
DOI: 10.1016/j.coph.2016.01.008 -
Gene Nov 2019Individual specific variable drug response against similar drugs raises a significant challenge for the effective and safe treatment of many human diseases.... (Review)
Review
Individual specific variable drug response against similar drugs raises a significant challenge for the effective and safe treatment of many human diseases. Pharmacogenomics is the branch which try to deal with these challenge by relating drug response to patient specific genome in order to better customize patient treatments. Pharmacogenomics based research focus on the whole genome, but since last few years after realizing the importance, it mainly centralized towards genes of pharmacological importance called pharmacogenes, and try to explore association between their variants and variable drug response in world's different population. This research was initiated with the resulted data from human genome based research projects and later on assisted by exome sequencing projects. Simultaneously, it was boost-up with the participation of various pharmacogenomics groups lead by PGRN. By realizing the significance of pharmacogenes, and their variant related information, in health science, scientific communities are already started to look for genes of pharmacogenomics importance with different aspect. This article aims to provide an inclusive insight on current state of knowledge of pharmacogenes, recent trends and progress in the understanding of the pharmacogenes and the implications for personalized medicine.
Topics: Genome, Human; Humans; Pharmacogenetics; Precision Medicine
PubMed: 31425740
DOI: 10.1016/j.gene.2019.144050 -
Alcoholism, Clinical and Experimental... Mar 2015Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the... (Review)
Review
BACKGROUND
Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects.
METHODS
This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy.
RESULTS
Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution.
CONCLUSIONS
Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD.
Topics: Alcohol-Related Disorders; Genetic Variation; Humans; Pharmacogenetics; Randomized Controlled Trials as Topic
PubMed: 25703505
DOI: 10.1111/acer.12643 -
Cold Spring Harbor Perspectives in... Feb 2019Inherited genetic variations in pharmacogenetic loci are widely acknowledged as important determinants of phenotypic differences in drug response, and may be actionable... (Review)
Review
Inherited genetic variations in pharmacogenetic loci are widely acknowledged as important determinants of phenotypic differences in drug response, and may be actionable in the clinic. However, recent studies suggest that a considerable number of novel rare variants in pharmacogenes likely contribute to a still unexplained fraction of the observed interindividual variability. Next-generation sequencing (NGS) represents a rapid, relatively inexpensive, large-scale DNA sequencing technology with potential relevance as a comprehensive pharmacogenetic genotyping platform to identify genetic variation related to drug therapy. However, many obstacles remain before the clinical use of NGS-based test results, including technical challenges, functional interpretation, and strict requirements for diagnostic tests. Advanced computational analyses, high-throughput screening methodologies, and generation of shared resources with cell-based and clinical information will facilitate the integration of NGS data into candidate genotyping approaches, likely enhancing future drug phenotype predictions in patients.
Topics: Computational Biology; Genetic Variation; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Pharmacogenetics; Phenotype; Sequence Analysis, DNA
PubMed: 29844222
DOI: 10.1101/cshperspect.a033027