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 (ELISA). 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=5x10−8. 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 identification of variants with suggestive associations in the discovery cohort (α=1x10−4). The top variant in both cohorts was rs1555175145 (discovery β=−0.112[0.018], p=2.50x10−5; replication β=−0.104[0.051], p=0.041). In gene set enrichment analysis (GSEA), three gene sets reached false discovery rate-adjusted significance (q