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
Thromb Haemost. 2015 113 (4): 772-81

PMID: 25503805 · PMCID: PMC4433536 · DOI:10.1160/TH14-08-0670

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.

MeSH Terms (25)

Adult Aged Antibodies Anticoagulants Biological Specimen Banks Chi-Square Distribution Electronic Health Records Female Genetic Predisposition to Disease Genome-Wide Association Study Heparin HLA-DR alpha-Chains 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

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