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

Media type: E-Article

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

Contributor: Giles, Jason B.; Steiner, Heidi E.; Rollin, Jerome; Shaffer, Christian M.; Momozawa, Yukihide; Mushiroda, Taisei; Inai, Chihiro; Selleng, Kathleen; Thiele, Thomas; Pouplard, Claire; Heddle, Nancy M.; Kubo, Michiaki; Miller, Elise C.; Martinez, Kiana L.; Phillips, Elizabeth J.; Warkentin, Theodore E.; Gruel, Yves; Greinacher, Andreas; Roden, Dan M.; Karnes, Jason H.

imprint: American Society of Hematology, 2022

Language: English

DOI: 10.1182/bloodadvances.2022007673

ISSN: 2473-9529; 2473-9537

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Footnote:

Description: 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 = 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 β = −0.112 [0.018], P = 2.50 × 10−5; replication β = −0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q &lt; 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.

Access State: Open Access

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