Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.
Blood. 2022 Jul 21;140(3):274-284. doi: 10.1182/blood.2021014240.
Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10-8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10-209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10-9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.
肝素诱导的血小板减少症（HIT）是一种不可预测的、潜在灾难性的不良反应，是由血小板因子 4（PF4）/肝素复合物引起的免疫反应引起的。我们在一个大型发现队列中进行了全基因组关联研究（GWAS），该队列将阳性功能测定作为结局，分为 3 组：（1）功能测定阳性病例（n=1269），（2）抗体阳性（功能测定阴性）对照（n=1131）和（3）抗体阴性对照（n=1766）。在功能测定确认的 HIT 病例（n=177）、抗体阳性（功能测定阴性）对照（n=258）和抗体阴性对照（n=351）的复制队列中（α=0.05）进行了具有显著关联的研究（α=5×10-8）。我们观察到阳性功能测定与 PF4/肝素免疫球蛋白-G（IgG）水平升高（比值比[OR]，16.53；95%置信区间[CI]，13.83-19.74；P=1.51×10-209）和女性性别（OR，1.15；95%CI，1.01-1.32；P=0.034）之间存在强烈关联。ABO 中的 rs8176719C 插入变体在发现队列中与阳性功能测定状态显著相关（频率=0.41；OR，0.751；95%CI，0.682-0.828；P=7.80×10-9）和复制队列（OR，0.467；95%CI，0.228-0.954；P=0.0367）。rs8176719C 插入，可编码所有非-O 血型等位基因，具有保护作用，表明 rs8176719C 缺失和 O 血型是 HIT 的危险因素（O 血型 OR，1.42；95%CI，1.26-1.61；P=3.09×10-8）。荟萃分析表明，ABO 关联独立于 PF4/肝素 IgG 水平，并且当将功能测定阳性病例与抗体阳性（功能测定阴性）对照相比与抗体阴性对照相比时，其关联更强。ABO 的测序和精细映射表明，rs8176719 是因果单核苷酸多态性（SNP）。我们的研究结果阐明了 HIT 发病机制的生物学基础，为预测提供了依据，并可能对相关疾病（如疫苗诱导的血栓性血小板减少症）具有重要意义。
