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

Abstract

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 5 4237) and replication cohort (n 5 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at a 5 5 3 1028. 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 (a 5 1 3 1024). The top variant in both cohorts was rs1555175145 (discovery b 5 20.112 [0.018], P 5 2.50 3 1025; replication b 5 20.104 [0.051], P 5 .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.