A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record

Jason H. Karnes, Robert M. Cronin, Jerome Rollin, Alexander Teumer, Claire Pouplard, Christian M. Shaffer, Carmelo Blanquicett, Erica A. Bowton, James D. Cowan, Jonathan D. Mosley, Sara L. van Driest, Peter E. Weeke, Quinn S. Wells, Tamam Bakchoul, Joshua C. Denny, Andreas Greinacher, Yves Gruel, Dan M. Roden

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)772-781
Number of pages10
JournalThrombosis and Haemostasis
Volume113
Issue number4
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Heparins
  • Pharamacogenetics
  • Thrombocytopenia

ASJC Scopus subject areas

  • Hematology

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    Karnes, J. H., Cronin, R. M., Rollin, J., Teumer, A., Pouplard, C., Shaffer, C. M., Blanquicett, C., Bowton, E. A., Cowan, J. D., Mosley, J. D., van Driest, S. L., Weeke, P. E., Wells, Q. S., Bakchoul, T., Denny, J. C., Greinacher, A., Gruel, Y., & Roden, D. M. (2015). A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record. Thrombosis and Haemostasis, 113(4), 772-781. https://doi.org/10.1160/TH14-08-0670