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A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record.
Karnes JH, Cronin RM, Rollin J, Teumer A, Pouplard C, Shaffer CM, Blanquicett C, Bowton EA, Cowan JD, Mosley JD, Van Driest SL, Weeke PE, Wells QS, Bakchoul T, Denny JC, Greinacher A, Gruel Y, Roden DM
(2015) Thromb Haemost 113: 772-81
MeSH Terms: Adult, Aged, Antibodies, Anticoagulants, Biological Specimen Banks, Chi-Square Distribution, Electronic Health Records, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DR alpha-Chains, Heparin, Humans, Linear Models, Logistic Models, Male, Middle Aged, Odds Ratio, Phenotype, Platelet Factor 4, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Retrospective Studies, Risk Factors, Thrombocytopenia
Show Abstract · Added January 23, 2015
Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. No genome-wide evaluations have been performed to identify potential genetic influences on HIT. Here, we performed a genome-wide association study (GWAS) and candidate gene study using HIT cases and controls identified using electronic medical records (EMRs) coupled to a DNA biobank and attempted to replicate GWAS associations in an independent cohort. We subsequently investigated influences of GWAS-associated single nucleotide polymorphisms (SNPs) on PF4/heparin antibodies in non-heparin treated individuals. In a recessive model, we observed significant SNP associations (odds ratio [OR] 18.52; 95% confidence interval [CI] 6.33-54.23; p=3.18×10(-9)) with HIT near the T-Cell Death-Associated Gene 8 (TDAG8). These SNPs are in linkage disequilibrium with a missense TDAG8 SNP. TDAG8 SNPs trended toward an association with HIT in replication analysis (OR 5.71; 0.47-69.22; p=0.17), and the missense SNP was associated with PF4/heparin antibody levels and positive PF4/heparin antibodies in non-heparin treated patients (OR 3.09; 1.14-8.13; p=0.02). In the candidate gene study, SNPs at HLA-DRA were nominally associated with HIT (OR 0.25; 0.15-0.44; p=2.06×10(-6)). Further study of TDAG8 and HLA-DRA SNPs is warranted to assess their influence on the risk of developing HIT.
0 Communities
3 Members
0 Resources
25 MeSH Terms
Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A.
Gialitakis M, Kretsovali A, Spilianakis C, Kravariti L, Mages J, Hoffmann R, Hatzopoulos AK, Papamatheakis J
(2006) Nucleic Acids Res 34: 765-72
MeSH Terms: Acetylation, Antineoplastic Agents, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA-Binding Proteins, Enhancer Elements, Genetic, Enzyme Inhibitors, Gene Expression Profiling, Genes, MHC Class II, HLA-DR Antigens, HLA-DR alpha-Chains, HeLa Cells, Histone Deacetylase Inhibitors, Histones, Humans, Hydroxamic Acids, Regulatory Factor X Transcription Factors, Transcription Factors, Transcriptional Activation
Show Abstract · Added November 18, 2010
The deacetylase inhibitor Trichostatin A (TSA) induces the transcription of the Major Histocompatibility Class II (MHC II) DRA gene in a way independent of the master coactivator CIITA. To analyze the molecular mechanisms by which this epigenetic regulator stimulates MHC II expression, we used chromatin immunoprecipitation (ChIP) assays to monitor the alterations in histone modifications that correlate with DRA transcription after TSA treatment. We found that a dramatic increase in promoter linked histone acetylation is followed by an increase in Histone H3 lysine 4 methylation and a decrease of lysine 9 methylation. Fluorescence recovery after photobleaching (FRAP) experiments showed that TSA increases the mobility of HDAC while decreasing the mobility of the class II enhanceosome factor RFX5. These data, in combination with ChIP experiments, indicate that the TSA-mediated induction of DRA transcription involves HDAC relocation and enhanceosome stabilization. In order to gain a genome-wide view of the genes responding to inhibition of deacetylases, we compared the transcriptome of B cells before and after TSA treatment using Affymetrix microarrays. This analysis showed that in addition to the DRA gene, the entire MHC II family and the adjacent histone cluster that are located in chromosome 6p21-22 locus are strongly induced by TSA. A complex pattern of gene reprogramming by TSA involves immune recognition, antiviral, apoptotic and inflammatory pathways and extends the rationale for using Histone Deacetylase Inhibitors (HDACi) to modulate the immune response.
1 Communities
1 Members
0 Resources
19 MeSH Terms