title: A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record.
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.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Karnes
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cronin
authors.forename: Jerome
authors.initials: J
authors.lastname: Rollin
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Claire
authors.initials: C
authors.lastname: Pouplard
authors.forename: Christian M
authors.initials: CM
authors.lastname: Shaffer
authors.forename: Carmelo
authors.initials: C
authors.lastname: Blanquicett
authors.forename: Erica A
authors.initials: EA
authors.lastname: Bowton
authors.forename: James D
authors.initials: JD
authors.lastname: Cowan
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.forename: Sara L
authors.initials: SL
authors.lastname: Van Driest
authors.forename: Peter E
authors.initials: PE
authors.lastname: Weeke
authors.forename: Quinn S
authors.initials: QS
authors.lastname: Wells
authors.forename: Tamam
authors.initials: T
authors.lastname: Bakchoul
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: Yves
authors.initials: Y
authors.lastname: Gruel
authors.affiliation: Dan M. Roden, MD, MRB4 1285B, 2215B Garland Avenue, Nashville, TN, 37232-0575, USA, Tel.: +1 615 322 0067, Fax: +1 615 343 4522, E-mail: dan.roden@Vanderbilt.Edu.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000925:Anticoagulants / Q000009:adverse effects* / Q000276:immunology; D018070:Biological Specimen Banks; D016009:Chi-Square Distribution; D057286:Electronic Health Records; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059805:HLA-DR alpha-Chains / Q000235:genetics; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D010978:Platelet Factor 4 / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology
chemical_list: D000906:Antibodies; D000925:Anticoagulants; C513334:GPR65 protein, human; D059805:HLA-DR alpha-Chains; D043562:Receptors, G-Protein-Coupled; D010978:Platelet Factor 4; D006493:Heparin
keywords: Pharamacogenetics; heparins; thrombocytopenia