Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia.
Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia.
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DOI：
10.1182/bloodadvances.2022007673
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发表时间：
2022-07-26
期刊：
影响因子：
7.5
通讯作者：
Karnes, Jason H.
中科院分区：
文献类型：
--
作者：
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.
在欧洲血统个体中，没有变体与全基因组显著性水平的抗PF 4/肝素抗体水平相关。我们的数据表明，遗传变异不是疑似HIT患者抗PF 4/肝素抗体水平的主要驱动因素。肝素是一种广泛使用的抗凝剂，具有抗体介导的药物不良反应肝素诱导的血小板减少症（HIT）的风险。肝素治疗患者的一个亚组产生可检测水平的抗体，抗肝素结合循环血小板因子4（PF 4）的复合物。使用全基因组关联研究（GWAS）方法，我们旨在鉴定与抗PF 4/肝素抗体相关的遗传变异，这些变异可解释HIT中观察到的可变抗体应答。我们对通过多克隆酶联免疫吸附试验测定的抗PF 4/肝素抗体水平进行了GWAS。我们的发现队列（n = 4237）和复制队列（n = 807）由欧洲血统和临床疑似HIT的患者组成，病例通过功能测定证实。在α = 5 × 10−8时考虑全基因组显著性。在发现队列中，在全基因组显著水平下，没有变体与抗PF 4/肝素抗体水平显著相关。次要GWAS分析包括在发现队列中识别具有提示性关联的变体（α = 1 × 10−4）。两个队列中最高的变异是rs 1555175145（发现β =-0.112 [0.018]，P = 2.50 × 10−5;复制β =-0.104 [0.051]，P = 0.041）。在基因集富集分析中，3个基因集在发现和复制群组中均达到假发现率调整的显著性（q < 0.05）：“白细胞跨内皮迁移”、“先天免疫应答”和“裂解酶活性”。我们的研究结果表明，基因组变异与抗PF 4/肝素抗体水平无显著相关性。鉴于我们能够识别具有中等频率和效应大小的变异，该证据表明遗传变异不是肝素治疗的欧洲血统患者中可变抗体应答的主要驱动因素。
No variants were associated with anti-PF4/heparin antibody levels at a genome-wide significance level in European ancestry individuals. Our data suggest that genetic variants are not primary drivers of anti-PF4/heparin antibody levels in patients suspected of HIT. 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.
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