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Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment.
Lewis TR, Shelton EL, Van Driest SL, Kannankeril PJ, Reese J
(2018) Semin Fetal Neonatal Med 23: 232-238
MeSH Terms: Acetaminophen, Animals, Disease Models, Animal, Ductus Arteriosus, Patent, Genetic Predisposition to Disease, Humans, Ibuprofen, Indomethacin, Infant, Newborn, Infant, Premature, Pharmacogenetics
Show Abstract · Added March 31, 2018
Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery.
Copyright © 2018 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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11 MeSH Terms
2017 Presidential Address: Checking, Balancing, and Celebrating Diversity: Celebrating Some of the Women Who Paved the Way.
Cox NJ
(2018) Am J Hum Genet 102: 342-349
MeSH Terms: Biography as Topic, Cultural Diversity, History, 20th Century, History, 21st Century, Human Genetics, Humans, Women
Added March 15, 2018
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1 Members
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7 MeSH Terms
Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects.
Volpi S, Bult CJ, Chisholm RL, Deverka PA, Ginsburg GS, Jacob HJ, Kasapi M, McLeod HL, Roden DM, Williams MS, Green ED, Rodriguez LL, Aronson S, Cavallari LH, Denny JC, Dressler LG, Johnson JA, Klein TE, Leeder JS, Piquette-Miller M, Perera M, Rasmussen-Torvik LJ, Rehm HL, Ritchie MD, Skaar TC, Wagle N, Weinshilboum R, Weitzel KW, Wildin R, Wilson J, Manolio TA, Relling MV
(2018) Clin Pharmacol Ther 103: 778-786
MeSH Terms: Humans, Pharmacogenetics, Precision Medicine, Research, United States
Show Abstract · Added March 14, 2018
Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them.
© 2018 American Society for Clinical Pharmacology and Therapeutics.
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5 MeSH Terms
Benefit of Preemptive Pharmacogenetic Information on Clinical Outcome.
Roden DM, Van Driest SL, Mosley JD, Wells QS, Robinson JR, Denny JC, Peterson JF
(2018) Clin Pharmacol Ther 103: 787-794
MeSH Terms: Drug Prescriptions, Genetic Variation, Genotype, Humans, Pharmacogenetics, Pharmacogenomic Testing
Show Abstract · Added March 14, 2018
The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to improve the outcome of drug therapy. Two broad approaches have been taken: a point-of-care approach in which genotyping for specific variant(s) is undertaken at the time of drug prescription, and a preemptive approach in which multiple genetic variants are typed in an individual patient and the information archived for later use when a drug with a "pharmacogenetic story" is prescribed. This review addresses the current state of implementation, the rationale for these approaches, and barriers that must be overcome. Benefits to pharmacogenetic testing are only now being defined and will be discussed.
© 2018 American Society for Clinical Pharmacology and Therapeutics.
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2 Members
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6 MeSH Terms
Local ancestry transitions modify snp-trait associations.
Fish AE, Crawford DC, Capra JA, Bush WS
(2018) Pac Symp Biocomput 23: 424-435
MeSH Terms: Adult, African Continental Ancestry Group, Chromosomes, Human, Computational Biology, Epistasis, Genetic, European Continental Ancestry Group, Evolution, Molecular, Gene Frequency, Genetics, Population, Genome-Wide Association Study, Haplotypes, Humans, Linear Models, Models, Genetic, Polymorphism, Single Nucleotide, Recombination, Genetic
Show Abstract · Added March 14, 2018
Genomic maps of local ancestry identify ancestry transitions - points on a chromosome where recent recombination events in admixed individuals have joined two different ancestral haplotypes. These events bring together alleles that evolved within separate continential populations, providing a unique opportunity to evaluate the joint effect of these alleles on health outcomes. In this work, we evaluate the impact of genetic variants in the context of nearby local ancestry transitions within a sample of nearly 10,000 adults of African ancestry with traits derived from electronic health records. Genetic data was located using the Metabochip, and used to derive local ancestry. We develop a model that captures the effect of both single variants and local ancestry, and use it to identify examples where local ancestry transitions significantly interact with nearby variants to influence metabolic traits. In our most compelling example, we find that the minor allele of rs16890640 occuring on a European background with a downstream local ancestry transition to African ancestry results in significantly lower mean corpuscular hemoglobin and volume. This finding represents a new way of discovering genetic interactions, and is supported by molecular data that suggest changes to local ancestry may impact local chromatin looping.
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16 MeSH Terms
The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.
Denny JC, Van Driest SL, Wei WQ, Roden DM
(2018) Clin Pharmacol Ther 103: 409-418
MeSH Terms: Big Data, Drug Repositioning, Electronic Health Records, Humans, Pharmacogenetics, Pharmacology, Clinical, Precision Medicine, Randomized Controlled Trials as Topic
Show Abstract · Added March 14, 2018
Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine.
© 2017 American Society for Clinical Pharmacology and Therapeutics.
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8 MeSH Terms
Genome-wide and Phenome-wide Approaches to Understand Variable Drug Actions in Electronic Health Records.
Robinson JR, Denny JC, Roden DM, Van Driest SL
(2018) Clin Transl Sci 11: 112-122
MeSH Terms: Biological Variation, Population, Computational Biology, Drug Discovery, Drug Repositioning, Drug-Related Side Effects and Adverse Reactions, Electronic Health Records, Genome, Genome-Wide Association Study, Humans, Molecular Targeted Therapy, Pharmacogenetics, Phenotype, Polymorphism, Single Nucleotide, Treatment Outcome
Added March 14, 2018
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2 Members
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14 MeSH Terms
Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.
Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, Kimmel SE, McDonough CW, Gong Y, Dave CV, Pratt VM, Alestock TD, Anderson RD, Alsip J, Ardati AK, Brott BC, Brown L, Chumnumwat S, Clare-Salzler MJ, Coons JC, Denny JC, Dillon C, Elsey AR, Hamadeh IS, Harada S, Hillegass WB, Hines L, Horenstein RB, Howell LA, Jeng LJB, Kelemen MD, Lee YM, Magvanjav O, Montasser M, Nelson DR, Nutescu EA, Nwaba DC, Pakyz RE, Palmer K, Peterson JF, Pollin TI, Quinn AH, Robinson SW, Schub J, Skaar TC, Smith DM, Sriramoju VB, Starostik P, Stys TP, Stevenson JM, Varunok N, Vesely MR, Wake DT, Weck KE, Weitzel KW, Wilke RA, Willig J, Zhao RY, Kreutz RP, Stouffer GA, Empey PE, Limdi NA, Shuldiner AR, Winterstein AG, Johnson JA, IGNITE Network
(2018) JACC Cardiovasc Interv 11: 181-191
MeSH Terms: Aged, Clinical Decision-Making, Clopidogrel, Cytochrome P-450 CYP2C19, Drug Resistance, Female, Humans, Male, Middle Aged, Patient Selection, Percutaneous Coronary Intervention, Pharmacogenetics, Pharmacogenomic Testing, Pharmacogenomic Variants, Platelet Aggregation Inhibitors, Prasugrel Hydrochloride, Predictive Value of Tests, Risk Assessment, Risk Factors, Ticagrelor, Time Factors, Treatment Outcome, United States
Show Abstract · Added March 14, 2018
OBJECTIVES - This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).
BACKGROUND - CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.
METHODS - After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.
RESULTS - Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).
CONCLUSIONS - These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Evidence of selection on splicing-associated loci in human populations and relevance to disease loci mapping.
Gamazon ER, Konkashbaev A, Derks EM, Cox NJ, Lee Y
(2017) Sci Rep 7: 5980
MeSH Terms: Chromosome Mapping, Disease, Genetic Loci, Genetics, Population, Genome-Wide Association Study, Humans, Introns, Nucleotide Motifs, Polymorphism, Single Nucleotide, RNA Splicing, Selection, Genetic
Show Abstract · Added October 27, 2017
We performed a whole-genome scan of genetic variants in splicing regulatory elements (SREs) and evaluated the extent to which natural selection has shaped extant patterns of variation in SREs. We investigated the degree of differentiation of single nucleotide polymorphisms (SNPs) in SREs among human populations and applied long-range haplotype- and multilocus allelic differentiation-based methods to detect selection signatures. We describe an approach, sampling a large number of loci across the genome from functional classes and using the consensus from multiple tests, for identifying candidates for selection signals. SRE SNPs in various SNP functional classes show different patterns of population differentiation compared with their non-SRE counterparts. Intronic regions display a greater enrichment for extreme population differentiation among the potentially tissue-dependent transcript ratio quantitative trait loci (trQTLs) than SRE SNPs in general and includ outlier trQTLs for cross-population composite likelihood ratio, suggesting that incorporation of context annotation for regulatory variation may lead to improved detection of signature of selection on these loci. The proportion of extremely rare SNPs disrupting SREs is significantly higher in European than in African samples. The approach developed here will be broadly useful for studies of function and disease-associated variation in the human genome.
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11 MeSH Terms
The Relation Between Inflation in Type-I and Type-II Error Rate and Population Divergence in Genome-Wide Association Analysis of Multi-Ethnic Populations.
Derks EM, Zwinderman AH, Gamazon ER
(2017) Behav Genet 47: 360-368
MeSH Terms: Genetics, Population, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide
Show Abstract · Added April 13, 2017
Population divergence impacts the degree of population stratification in Genome Wide Association Studies. We aim to: (i) investigate type-I error rate as a function of population divergence (F) in multi-ethnic (admixed) populations; (ii) evaluate the statistical power and effect size estimates; and (iii) investigate the impact of population stratification on the results of gene-based analyses. Quantitative phenotypes were simulated. Type-I error rate was investigated for Single Nucleotide Polymorphisms (SNPs) with varying levels of F between the ancestral European and African populations. Type-II error rate was investigated for a SNP characterized by a high value of F. In all tests, genomic MDS components were included to correct for population stratification. Type-I and type-II error rate was adequately controlled in a population that included two distinct ethnic populations but not in admixed samples. Statistical power was reduced in the admixed samples. Gene-based tests showed no residual inflation in type-I error rate.
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4 MeSH Terms