Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia.

Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10-8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10-4). The top variant in both cohorts was rs1555175145 (discovery ß = -0.112 [0.018], P = 2.50 × 10-5; replication ß = -0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: "Leukocyte Transendothelial Migration," "Innate Immune Response," and "Lyase Activity." Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.

Elucidation of Cellular Contributions to Heparin-Induced Thrombocytopenia Using Omic Approaches.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, complex, immune-mediated adverse drug reaction associated with a high mortality. Despite decades of research into HIT, fundamental knowledge gaps persist regarding HIT likely due to the complex and unusual nature of the HIT immune response. Such knowledge gaps include the identity of a HIT immunogen, the intrinsic roles of various cell types and their interactions, and the molecular basis that distinguishes pathogenic and non-pathogenic PF4/heparin antibodies. While a key feature of HIT, thrombocytopenia, implicates platelets as a seminal cell fragment in HIT pathogenesis, strong evidence exists for critical roles of multiple cell types. The rise in omic technologies over the last decade has resulted in a number of agnostic, whole system approaches for biological research that may be especially informative for complex phenotypes. Applying multi-omics techniques to HIT has the potential to bring new insights into HIT pathophysiology and identify biomarkers with clinical utility. In this review, we review the clinical, immunological, and molecular features of HIT with emphasis on key cell types and their roles. We then address the applicability of several omic techniques underutilized in HIT, which have the potential to fill knowledge gaps related to HIT biology.