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 = 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 < 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.

• Authors: Jason B Giles, Heidi E Steiner, Jerome Rollin, Christian M Shaffer, Yukihide Momozawa, Taisei Mushiroda, Chihiro Inai, Kathleen Selleng, Thomas Thiele, Claire Pouplard, Nancy M Heddle, Michiaki Kubo, Elise C Miller, Kiana L Martinez, Elizabeth J Phillips, Theodore E Warkentin, Yves Gruel, Andreas Greinacher, Dan M Roden, Jason H Karnes
• Journal: Blood advances (Blood Adv) Vol. 6 Issue 14 Pg. 4137-4146 (07 26 2022) ISSN: 2473-9537 [Electronic] United States
• PMID: 35533259 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Antibodies
• Immunologic Factors
• Platelet Factor 4
• Heparin

Topics

• Antibodies
• Genome-Wide Association Study
• Heparin (adverse effects)
• Humans
• Immunologic Factors (adverse effects)
• Platelet Factor 4 (genetics)
• Thrombocytopenia (chemically induced, genetics)