Abstract 13476: Association of HLA-DRB3*01:01 With Heparin-Induced Thrombocytopenia

Abstract

Introduction: Variation in the human leukocyte antigen (HLA) region is now used clinically to prevent immune-mediated adverse drug reactions. Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin treatment. Previous studies have implicated HLA-DR variants in HIT, but HLA alleles which predispose patients to HIT have not been identified. Hypothesis: Our hypothesis is that sequenced HLA alleles are associated with HIT. Methods: We identified HIT cases and heparin-exposed controls in an electronic medical record coupled to a DNA biobank. Cases were defined based on HIT antibody results, HIT risk scoring (4Ts score), and serotonin release assay results. Controls were matched to cases based on age, gender, and type of heparin exposure (unfractionated versus low molecular weight heparin). We performed high resolution, four-digit HLA sequencing for HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DP, and HLA-DQ using long-read 454 FLX sequencing. We tested association of sequenced HLA alleles using conditional univariate logistic regression in a dominant model. Analysis was restricted to individuals with European ancestry and HLA alleles with a frequency greater than 0.01 (n=101). P values were corrected using a Bonferroni correction for 101 sequenced HLA alleles (alpha=4.95x10 -4 ). Results: We identified 77 HIT cases and 345 matched controls. No statistical differences were observed between cases and controls for baseline characteristics. The HLA-DRB3*01:01 allele was significantly associated with HIT (odds ratio 3.55, p=1.09x10 -4 ). No other alleles showed a significant association with HIT. Conclusions: We implicate the HLA-DRB3*01:01 allele as a risk factor for HIT. This allele represents a biologically plausible candidate for HIT, considering the previous literature implicating HLA-DR variation in HIT, the central role of HLA-DR in T cell-dependent antibody production, and the importance of T cells in HIT pathogenesis. Validation of HLA-DRB3*01:01 as a predictor of HIT pathogenesis would lead to preventive genotyping to reduce the risk of HIT.