J. H. Karnes, J. C. Denny, E. A. Bowton, C. M. Shaffer, J. D. Mosley, S. Van Driest, P. E. Weeke, Q. S. Wells, D. M. Roden; Vanderbilt University, Nashville, TN

BACKGROUND: Heparin induced thrombocytopenia (HIT) is an unpredictable potentially catastrophic reaction to heparin that is dependent on platelet factor 4/heparin antibody (PF4/Hep Ab) formation. Five single nucleotide polymorphisms (SNPs) have been previously associated with HIT but SNP influences on PF4/Hep Ab formation have not been systematically examined.
METHODS: We identified heparin-treated patients with a PF4/Hep Ab test result in BioVU, an electronic medical record coupled to a DNA biobank. Cases were individuals with positive or equivocal PF4/Hep Ab results, and individuals with negative PF4/Hep Ab results were considered controls. Samples were genotyped using Illumina HumanOmniQUAD platforms followed by quality control and genotype imputation. Logistic regressions were performed with adjustment for age, gender, and first two principal components in an additive genetic model. Significance was considered at α=5.0x10-8 for novel SNP associations and p=0.01 for five previously observed SNP associations.
RESULTS: We identified 108 cases and 197 controls. No novel SNPs reached the significance threshold. The strongest association was observed for the SNP rs11248979 (OR 3.03, p=1.44x10-6) upstream of the Rh blood group D antigen gene (RHD). Two SNPs previously associated with HIT were significantly associated with PF4/Hep Ab formation, including rs7529425 in FCGR2A (OR 2.19, p=0.003) and rs9268615 in HLA-DR (OR 1.66, p=0.003).
CONCLUSION: We replicate associations for two SNPs, suggesting a true association with HIT and implicating HIT associated SNPs with PF4/Hep Ab formation. We also observed a suggestive association in RHD. Further study is warranted to test the clinical utility of replicated SNPs in HIT prediction and to confirm the role of RHD in PF4/Hep Ab formation.