Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 32

Publication Record


is associated with indomethacin treatment failure for patent ductus arteriosus.
Rooney SR, Shelton EL, Aka I, Shaffer CM, Clyman RI, Dagle JM, Ryckman K, Lewis TR, Reese J, Van Driest SL, Kannankeril PJ
(2019) Pharmacogenomics 20: 939-946
MeSH Terms: Cohort Studies, Cyclooxygenase Inhibitors, Cytochrome P-450 CYP2C9, Ductus Arteriosus, Patent, Female, Gestational Age, Humans, Indomethacin, Infant, Infant, Newborn, Infant, Premature, Male, Treatment Failure, Treatment Outcome
Show Abstract · Added July 28, 2020
To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). This is a multicenter cohort study of 144 preterm infants (22-32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60-0.96), surfactant use (AOR 9.77, 95% CI 1.15-83.26), and (AOR 3.74; 95% CI 1.34-10.44) were each associated with indomethacin failure. Age, surfactant use, and influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.
0 Communities
1 Members
0 Resources
MeSH Terms
High and variable population prevalence of HLA-B*56:02 in indigenous Australians and relation to phenytoin-associated drug reaction with eosinophilia and systemic symptoms.
Somogyi AA, Barratt DT, Phillips EJ, Moore K, Ilyas F, Gabb GM
(2019) Br J Clin Pharmacol 85: 2163-2169
MeSH Terms: Adolescent, Adult, Aged, Australia, Biological Variation, Population, Cohort Studies, Cytochrome P-450 CYP2C9, Drug Hypersensitivity Syndrome, Female, Gene Frequency, Genetic Predisposition to Disease, Genotyping Techniques, HLA-B Antigens, Humans, Indigenous Peoples, Male, Middle Aged, Phenytoin, Young Adult
Show Abstract · Added March 30, 2020
Phenytoin drug reaction with eosinophilia and systemic symptoms (DRESS) in 3 Aboriginal Australians positive for HLA-B*56:02 has been previously reported. We report the allele frequency of HLA-B*56:02 in 2 South Australian populations, 1 Aboriginal (4.8%, 95% confidence interval 2.4-7.8%) and the other European (0%). We compared the frequency with publicly available information on HLA-B*56:02 status in other Indigenous Australian (n = 4) and European Australian cohorts (n = 1). In the Indigenous Australian cohorts, HLA-B*56:02 allele frequency ranged from 1.3 to 19%. We also describe an additional case of phenytoin DRESS (RegiSCAR DRESS score 7) in an Aboriginal Australian that was associated with HLA-B*56:02 and with CYP2C9*1/*3 genotype. In Aboriginal Australians, phenytoin DRESS appears distinctly linked to HLA-B*56:02 with an allele carriage rate substantially higher than in Europeans, but also with considerable regional variation. Investigations of human leucocyte antigen and other contributing genes and severe adverse drug reactions in understudied non-European populations are required to optimize safe medication use and inform risk mitigation strategies.
© 2019 The British Pharmacological Society.
0 Communities
1 Members
0 Resources
19 MeSH Terms
The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production.
Sausville LN, Gangadhariah MH, Chiusa M, Mei S, Wei S, Zent R, Luther JM, Shuey MM, Capdevila JH, Falck JR, Guengerich FP, Williams SM, Pozzi A
(2018) Cancer Res 78: 4865-4877
MeSH Terms: Animals, Arachidonic Acid, Arachidonic Acids, Carcinogenesis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Eicosanoids, Endothelial Cells, Humans, Mice, Polymorphism, Single Nucleotide, Xenograft Model Antitumor Assays
Show Abstract · Added October 25, 2018
Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants and encode proteins with reduced enzymatic activity, and individuals carrying these variants metabolize drugs more slowly than individuals with wild-type , potentially affecting their response to drugs and altering their risk of disease. Although genetic differences in CYP2C9-dependent oxidation of arachidonic acid (AA) have been reported, the roles of CYP2C9*2 and CYP2C9*3 in EET biosynthesis and their relevance to disease are unknown. Here, we report that CYP2C9*2 and CYP2C9*3 metabolize AA less efficiently than CYP2C9*1 and that they play a role in the progression of non-small cell lung cancer (NSCLC) via impaired EET biosynthesis. When injected into mice, NSCLC cells expressing CYP2C9*2 and CYP2C9*3 produced lower levels of EETs and developed fewer, smaller, and less vascularized tumors than cells expressing CYP2C9*1. Moreover, endothelial cells expressing these two variants proliferated and migrated less than cells expressing CYP2C*1. Purified CYP2C9*2 and CYP2C9*3 exhibited attenuated catalytic efficiency in producing EETs, primarily due to impaired reduction of these two variants by NADPH-P450 reductase. Loss-of-function SNPs within and were associated with improved survival in female cases of NSCLC. Thus, decreased EET biosynthesis represents a novel mechanism whereby CYPC29*2 and CYP2C9*3 exert a direct protective role in NSCLC development. These findings report single nucleotide polymorphisms in the human CYP2C9 genes, and , exert a direct protective role in tumorigenesis by impairing EET biosynthesis. .
©2018 American Association for Cancer Research.
0 Communities
2 Members
0 Resources
14 MeSH Terms
Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.
Hernandez W, Gamazon ER, Aquino-Michaels K, Smithberger E, O'Brien TJ, Harralson AF, Tuck M, Barbour A, Cavallari LH, Perera MA
(2017) J Thromb Haemost 15: 735-743
MeSH Terms: Adult, African Americans, Aged, Algorithms, Calcium-Binding Proteins, Cohort Studies, Cytochrome P-450 CYP2C9, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Genotype, Humans, Linkage Disequilibrium, Liver, Male, Middle Aged, Pharmacogenetics, Precision Medicine, Quantitative Trait Loci, Thromboembolism, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added April 13, 2017
Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation.
SUMMARY - Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research.
© 2017 International Society on Thrombosis and Haemostasis.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Wiley LK, Vanhouten JP, Samuels DC, Aldrich MC, Roden DM, Peterson JF, Denny JC
(2017) Pac Symp Biocomput 22: 545-556
MeSH Terms: Adult, African Americans, Aged, Algorithms, Anticoagulants, Cohort Studies, Computational Biology, Cytochrome P-450 CYP2C9, European Continental Ancestry Group, Female, Gene Frequency, Humans, Male, Middle Aged, Models, Genetic, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 14, 2018
The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. This study sought to determine if: 1) including additional variants associated with warfarin dose in African Americans, 2) predicting within single ancestry groups rather than a combined population, or 3) using percentage African ancestry rather than observed race, would improve warfarin dosing algorithms in African Americans. Using BioVU, the Vanderbilt University Medical Center biobank linked to electronic medical records, we compared 25 modeling strategies to existing algorithms using a cohort of 2,181 warfarin users (1,928 whites, 253 blacks). We found that approaches incorporating additional variants increased model accuracy, but not in clinically significant ways. Race stratification increased model fidelity for African Americans, but the improvement was small and not likely to be clinically significant. Use of percent African ancestry improved model fit in the context of race misclassification.
0 Communities
2 Members
0 Resources
19 MeSH Terms
Genetic determinants of variability in warfarin response after the dose-titration phase.
Iwuchukwu OF, Ramirez AH, Shi Y, Bowton EA, Kawai VK, Schildcrout JS, Roden DM, Denny JC, Stein CM
(2016) Pharmacogenet Genomics 26: 510-516
MeSH Terms: Adult, African Americans, Aged, Aged, 80 and over, Anticoagulants, Calcium-Binding Proteins, Carbon-Carbon Ligases, Cytochrome P-450 CYP2C9, Cytochrome P450 Family 4, Epoxide Hydrolases, European Continental Ancestry Group, Female, Humans, International Normalized Ratio, Male, Middle Aged, Pharmacogenomic Variants, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 14, 2018
OBJECTIVES - Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known.
METHODS - Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans.
RESULTS - One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR.
CONCLUSION - The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.
0 Communities
2 Members
0 Resources
19 MeSH Terms
Genotype and risk of major bleeding during warfarin treatment.
Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, Jiang M, Li C, Denny JC, Shaffer C, Bowton E, Gage BF, Ray WA, Roden DM, Stein CM
(2014) Pharmacogenomics 15: 1973-83
MeSH Terms: Adult, Aged, Biological Specimen Banks, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 4, Dose-Response Relationship, Drug, Ethnic Groups, Female, Gene Frequency, Genetic Association Studies, Genetic Variation, Genotype, Hemorrhage, Humans, Male, Middle Aged, Risk Factors, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added January 23, 2015
AIM - To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy.
MATERIALS & METHODS - Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy.
RESULTS - CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04).
CONCLUSION - The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.
0 Communities
4 Members
0 Resources
20 MeSH Terms
The role of cytochrome P450 epoxygenases in retinal angiogenesis.
Capozzi ME, McCollum GW, Penn JS
(2014) Invest Ophthalmol Vis Sci 55: 4253-60
MeSH Terms: Animals, Animals, Newborn, Aryl Hydrocarbon Hydroxylases, Astrocytes, Cell Proliferation, Cells, Cultured, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Disease Models, Animal, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Developmental, Humans, Microcirculation, RNA, Messenger, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Retina, Retinal Neovascularization, Vascular Endothelial Growth Factor A
Show Abstract · Added February 19, 2015
PURPOSE - The purpose of this study was to investigate the role(s) of cytochrome P450 epoxygenases (CYPs) and their products, the epoxyeicosatrienoic acids (EETs), in hypoxia-induced VEGF production and pathologic retinal angiogenesis.
METHODS - Human retinal astrocytes, Müller cells, and retinal microvascular endothelial cells (HRMEC) were exposed to hypoxia, and relative CYP2C expression was measured by RT-PCR. Astrocyte and Müller cell VEGF production was measured by ELISA after exposure to hypoxia and treatment with the general CYP inhibitor, SKF-525a. Human retinal microvascular endothelial cells were treated with the CYP product, 11,12-epoxyeicosatrienoic acid [EET], or SKF-525a in the presence or absence of VEGF. Proliferation of HRMEC and tube formation were assayed. Oxygen-induced retinopathy (OIR) was induced in newborn rats. Retinal CYP2C11 and CYP2C23 expression were measured by RT-PCR. The OIR rats received SKF-525a by intravitreal injection and preretinal neovascularization (NV) was quantified. Retinal VEGF protein levels were measured by ELISA.
RESULTS - Human retinal astrocytes were the only cells to exhibit significant induction of CYP2C8 and CYP2C9 mRNA expression by hypoxia. Astrocytes, but not Müller cells, exhibited reduced hypoxia-induced VEGF production when treated with SKF-525a. 11,12-EET induced HRMEC proliferation and tube formation, and SKF-525a inhibited VEGF-induced proliferation. Oxygen-induced retinopathy induced expression of CYP2C23, but had no effect on CYP2C11. SKF-525a inhibited retinal NV and reduced retinal VEGF levels in OIR rats.
CONCLUSIONS - The CYP-derived 11,12-EET may exhibit a proangiogenic biological function in the retina following stimulation by hypoxia in astrocytes. Inhibition of CYP may provide a rational therapy against retinal NV, because it can reduce VEGF production and VEGF-induced angiogenic responses in endothelial cells.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
1 Communities
1 Members
0 Resources
23 MeSH Terms
The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population.
Vear SI, Ayers GD, Van Driest SL, Sidonio RF, Stein CM, Ho RH
(2014) Br J Haematol 165: 832-5
MeSH Terms: Adolescent, Age Factors, Alleles, Anticoagulants, Aryl Hydrocarbon Hydroxylases, Child, Child, Preschool, Cross-Sectional Studies, Cytochrome P-450 CYP2C9, Genetic Variation, Genotype, Humans, Infant, Pharmacogenetics, Retrospective Studies, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 10, 2014
The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, P < 0·0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (P = 0·001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.
© 2014 John Wiley & Sons Ltd.
1 Communities
3 Members
0 Resources
17 MeSH Terms
Applied pharmacogenomics in cardiovascular medicine.
Weeke P, Roden DM
(2014) Annu Rev Med 65: 81-94
MeSH Terms: Adrenergic beta-Antagonists, Antihypertensive Agents, Antithrombins, Aryl Hydrocarbon Hydroxylases, Cardiovascular Diseases, Clopidogrel, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2C9, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver-Specific Organic Anion Transporter 1, Organic Anion Transporters, Pharmacogenetics, Polymorphism, Single Nucleotide, Precision Medicine, Ticlopidine, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 7, 2014
Interindividual heterogeneity in drug response is a central feature of all drug therapies. Studies in individual patients, families, and populations over the past several decades have identified variants in genes encoding drug elimination or drug target pathways that in some cases contribute substantially to variable efficacy and toxicity. Important associations of pharmacogenomics in cardiovascular medicine include clopidogrel and risk for in-stent thrombosis, steady-state warfarin dose, myotoxicity with simvastatin, and certain drug-induced arrhythmias. This review describes methods used to accumulate and validate these findings and points to approaches--now being put in place at some centers--to implementing them in clinical care.
0 Communities
1 Members
0 Resources
18 MeSH Terms