A genome-wide association study of heparin-induced thrombocyto - penia 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

doi:10.1160/TH14-08-0670

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(04): 772-781
DOI: 10.1160/TH14-08-0670

Coagulation and Fibrinolysis

Schattauer GmbH

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

Jason H. Karnes

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Robert M. Cronin

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Jerome Rollin

²UMR CNRS 7292 & University Hospital of Tours, Tours Cedex, France

,

Alexander Teumer

³University of Greifswald, Greifswald, Germany

,

Claire Pouplard

²UMR CNRS 7292 & University Hospital of Tours, Tours Cedex, France

,

Christian M. Shaffer

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Carmelo Blanquicett

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Erica A. Bowton

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

James D. Cowan

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Jonathan D. Mosley

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Sara L. Van Driest

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Peter E. Weeke

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

⁴Copenhagen University Hospital, Gentofte, Denmark

,

Quinn S. Wells

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Tamam Bakchoul

³University of Greifswald, Greifswald, Germany

,

Joshua C. Denny

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

,

Andreas Greinacher

³University of Greifswald, Greifswald, Germany

,

Yves Gruel

²UMR CNRS 7292 & University Hospital of Tours, Tours Cedex, France

,

Dan M. Roden

¹Vanderbilt University School of Medicine, Nashville, Tennessee, USA

› Author Affiliations

Abstract

Summary

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.

Keywords

Pharamacogenetics - heparins - thrombocytopenia

Full Text

References

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