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A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X during Infection.
Choby JE, Monteith AJ, Himmel LE, Margaritis P, Shirey-Rice JK, Pruijssers A, Jerome RN, Pulley J, Skaar EP
(2019) Infect Immun 87:
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Disease Models, Animal, Factor X, Host-Pathogen Interactions, Humans, Mice, Mice, Inbred C57BL, Phenotype, Polymorphism, Genetic
Show Abstract · Added April 7, 2019
Coagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemic infection, suggesting that factor X plays a role in the immune response to Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology of infection.
Copyright © 2019 American Society for Microbiology.
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11 MeSH Terms
CYP2D6 genotype and adverse events to risperidone in children and adolescents.
Oshikoya KA, Neely KM, Carroll RJ, Aka IT, Maxwell-Horn AC, Roden DM, Van Driest SL
(2019) Pediatr Res 85: 602-606
MeSH Terms: Adolescent, Alleles, Child, Cytochrome P-450 CYP2D6, Electronic Health Records, Female, Genotype, Humans, Male, Pharmacogenetics, Phenotype, Polymorphism, Genetic, Retrospective Studies, Risk, Risperidone, Treatment Outcome
Show Abstract · Added March 24, 2020
BACKGROUND - There are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children.
METHODS - Children ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers.
RESULTS - For analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03).
CONCLUSION - Children with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.
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16 MeSH Terms
The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine.
Fontana RJ, Cirulli ET, Gu J, Kleiner D, Ostrov D, Phillips E, Schutte R, Barnhart H, Chalasani N, Watkins PB, Hoofnagle JH
(2018) J Hepatol 69: 1317-1325
MeSH Terms: Adult, Aged, Alanine Transaminase, Alkaline Phosphatase, Antifungal Agents, Biomarkers, Chemical and Drug Induced Liver Injury, Cholestasis, Female, Follow-Up Studies, HLA-A Antigens, HLA-B14 Antigen, Haplotypes, Humans, Liver, Male, Middle Aged, Molecular Docking Simulation, Polymorphism, Genetic, Prospective Studies, Protein Binding, Terbinafine
Show Abstract · Added March 30, 2020
BACKGROUND & AIMS - Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01.
METHODS - Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform.
RESULTS - All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03.
CONCLUSIONS - Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians.
LAY SUMMARY - A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.
Copyright © 2018 European Association for the Study of the Liver. All rights reserved.
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Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.
Campbell JD, Yau C, Bowlby R, Liu Y, Brennan K, Fan H, Taylor AM, Wang C, Walter V, Akbani R, Byers LA, Creighton CJ, Coarfa C, Shih J, Cherniack AD, Gevaert O, Prunello M, Shen H, Anur P, Chen J, Cheng H, Hayes DN, Bullman S, Pedamallu CS, Ojesina AI, Sadeghi S, Mungall KL, Robertson AG, Benz C, Schultz A, Kanchi RS, Gay CM, Hegde A, Diao L, Wang J, Ma W, Sumazin P, Chiu HS, Chen TW, Gunaratne P, Donehower L, Rader JS, Zuna R, Al-Ahmadie H, Lazar AJ, Flores ER, Tsai KY, Zhou JH, Rustgi AK, Drill E, Shen R, Wong CK, Cancer Genome Atlas Research Network, Stuart JM, Laird PW, Hoadley KA, Weinstein JN, Peto M, Pickering CR, Chen Z, Van Waes C
(2018) Cell Rep 23: 194-212.e6
MeSH Terms: Carcinoma, Squamous Cell, Cell Line, Tumor, DNA Methylation, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Genomics, Humans, Metabolic Networks and Pathways, Polymorphism, Genetic
Show Abstract · Added October 30, 2019
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
Published by Elsevier Inc.
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Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species.
Lind AL, Wisecaver JH, Lameiras C, Wiemann P, Palmer JM, Keller NP, Rodrigues F, Goldman GH, Rokas A
(2017) PLoS Biol 15: e2003583
MeSH Terms: Alleles, Aspergillus fumigatus, Biological Evolution, Fungal Proteins, Fungi, Genetic Variation, Genome, Fungal, Genomics, Metabolic Networks and Pathways, Multigene Family, Mutation, Polymorphism, Genetic, Secondary Metabolism
Show Abstract · Added March 21, 2018
Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.
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13 MeSH Terms
Severe Delayed Drug Reactions: Role of Genetics and Viral Infections.
Pavlos R, White KD, Wanjalla C, Mallal SA, Phillips EJ
(2017) Immunol Allergy Clin North Am 37: 785-815
MeSH Terms: Antigens, Viral, Autoantigens, Cross Reactions, Drug-Related Side Effects and Adverse Reactions, Gene Frequency, Genetic Predisposition to Disease, Genotype, HLA Antigens, Humans, Immunologic Memory, Polymorphism, Genetic, Risk, T-Lymphocytes, Virus Diseases
Show Abstract · Added March 30, 2020
Adverse drug reactions (ADRs) are a significant source of patient morbidity and mortality and represent a major burden to health care systems and drug development. Up to 50% of such reactions are preventable. Although many ADRs can be predicted based on the on-target pharmacologic activity, ADRs arising from drug interactions with off-target receptors are recognized. Off-target ADRs include the immune-mediated ADRs (IM-ADRs) and pharmacologic drug effects. In this review, we discuss what is known about the immunogenetics and pathogenesis of IM-ADRs and the hypothesized role of heterologous immunity in the development of IM-ADRs.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery.
Shuey MM, Billings FT, Wei S, Milne GL, Nian H, Yu C, Brown NJ
(2017) PLoS One 12: e0175292
MeSH Terms: Acute Kidney Injury, Aged, Cohort Studies, Coronary Artery Bypass, Eicosapentaenoic Acid, Epoxide Hydrolases, Female, Genotype, Glomerular Filtration Rate, Humans, Incidence, Lysine, Male, Middle Aged, Polymorphism, Genetic
Show Abstract · Added November 7, 2018
Twenty to thirty percent of patients undergoing cardiac surgery develop acute kidney injury (AKI). In mice, inhibition of soluble epoxide hydrolase (sEH) attenuates renal injury following ischemia-reperfusion. We tested the hypothesis that functional variants of EPHX2, encoding sEH, are associated with AKI after cardiac surgery. We genotyped patients in two independent cardiac surgery cohorts for functional EPHX2 polymorphisms, Lys55Arg and Arg287Gln, and determined AKI using Acute Kidney Injury Network criteria. The 287Gln variant was not associated with AKI. In the discovery cohort, the gain-of-function 55Arg variant was associated with an increased incidence of AKI in univariate (p = 0.03) and multivariable (p = 0.04) analyses. In white patients without chronic kidney disease (CKD), the 55Arg variant was independently associated with AKI with an OR of 2.04 (95% CI 0.95-4.42) for 55Arg heterozygotes and 31.53 (1.57-633.19) for homozygotes (p = 0.02), after controlling for age, sex, body mass index, baseline estimated glomerular filtration rate, and use of cardiopulmonary bypass. These findings were replicated in the second cardiac surgery cohort. 12,13- and total- dihydroxyoctadecanoic acids (DiHOME): epoxyoctadecanoic acids (EpOME) ratios were increased in EPHX2 55Arg variant carriers, consistent with increased hydrolase activity. The EPHX2 Lys55Arg polymorphism is associated with AKI following cardiac surgery in patients without preexisting CKD. Pharmacological strategies to decrease sEH activity might decrease postoperative AKI.
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The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease.
Xie LJ, Cui Z, Chen FJ, Pei ZY, Hu SY, Gu QH, Jia XY, Zhu L, Zhou XJ, Zhang H, Liao YH, Lai LH, Hudson BG, Zhao MH
(2017) Immunology 151: 395-404
MeSH Terms: Alleles, Anti-Glomerular Basement Membrane Disease, Autoantigens, China, Collagen Type IV, Computer Simulation, Epitope Mapping, Epitopes, T-Lymphocyte, Genetic Predisposition to Disease, Genotype, HLA-DRB1 Chains, Humans, Polymorphism, Genetic, Protein Binding, Protein Conformation, Receptors, Antigen, T-Cell, Risk, T-Lymphocytes
Show Abstract · Added May 12, 2017
Goodpasture's disease is closely associated with HLA, particularly DRB1*1501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of α3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB1*1501 (OR = 4·6, P = 5·7 × 10 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4·0, P = 1·0 × 10 ) and proline at position 11 (PRO11) (OR = 4·0, P = 2·0 × 10 ) on DRβ1, encoded by DRB1*1501, were associated with disease susceptibility. α (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB1*1501. Isoleucine , tryptophan , glycine , phenylalanine and phenylalanine , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRβ1 chain and presenting T-cell epitope, α , with five critical residues.
© 2017 John Wiley & Sons Ltd.
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18 MeSH Terms
Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 100 Luo infants from the Boro area of Nyanza Province, Kenya.
Arlehamn CS, Copin R, Leary S, Mack SJ, Phillips E, Mallal S, Sette A, Blatner G, Siefers H, Ernst JD, TBRU-ASTRa Study Team
(2017) Hum Immunol 78: 325-326
MeSH Terms: Databases, Nucleic Acid, Gene Frequency, Genetics, Population, Genotype, HLA Antigens, Histocompatibility Testing, Humans, Infant, Kenya, Linkage Disequilibrium, Polymorphism, Genetic, Sequence Analysis, DNA
Show Abstract · Added March 30, 2020
One hundred healthy infants enrolled as controls in a tuberculosis vaccine study in Nyanza Province, Kenya provided anonymized samples for DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, -DRB1, and -DRB3/4/5 loci. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-B, -C, -DRB1, -DPB1, -DQA1 and -DQB1 loci. A minor deviation was detected at the HLA-A locus due to an excess of HLA-A*02:02, 29:02, 30:02, and 68:02 homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3393.
Copyright © 2017. Published by Elsevier Inc.
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Improvements and impacts of GRCh38 human reference on high throughput sequencing data analysis.
Guo Y, Dai Y, Yu H, Zhao S, Samuels DC, Shyr Y
(2017) Genomics 109: 83-90
MeSH Terms: Data Accuracy, Genome, Human, Genomic Library, Genomics, High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Genetic, Sequence Analysis, DNA
Show Abstract · Added April 18, 2017
Analyses of high throughput sequencing data starts with alignment against a reference genome, which is the foundation for all re-sequencing data analyses. Each new release of the human reference genome has been augmented with improved accuracy and completeness. It is presumed that the latest release of human reference genome, GRCh38 will contribute more to high throughput sequencing data analysis by providing more accuracy. But the amount of improvement has not yet been quantified. We conducted a study to compare the genomic analysis results between the GRCh38 reference and its predecessor GRCh37. Through analyses of alignment, single nucleotide polymorphisms, small insertion/deletions, copy number and structural variants, we show that GRCh38 offers overall more accurate analysis of human sequencing data. More importantly, GRCh38 produced fewer false positive structural variants. In conclusion, GRCh38 is an improvement over GRCh37 not only from the genome assembly aspect, but also yields more reliable genomic analysis results.
Copyright © 2017. Published by Elsevier Inc.
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8 MeSH Terms