Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia Academic Article uri icon

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abstract

  • 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

  • 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
  • Kubo, Michiaki
  • Miller, Elise C
  • Martinez, Kiana L
  • Phillips, Elizabeth J
  • Warkentin, Theodore E
  • Gruel, Yves
  • Greinacher, Andreas
  • Roden, Dan M
  • Karnes, Jason H

publication date

  • July 26, 2022