부산대학교 도서관

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 with positive functional assay as the outcome in a large discovery cohort of patients divided into three 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 (alpha=5x10-8) were investigated in a replication cohort (alpha=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 IgG level (odds ratio [OR] 16.53[95% confidence interval 13.83-19.74], p=1.51x10-209) and female sex (OR 1.15[1.01-1.32], p=0.034). The rs8176719 C insertion variant in ABOwas significantly associated with positive functional assay status in the discovery cohort (frequency=0.41; OR 0.751[0.682-0.828], p=7.80x10-9) and in the replication cohort (OR 0.467 [0.228-0.954], p=0.0367). 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 was a risk factor for HIT (O blood group OR 1.42 [1.26-1.61], p=3.09x10-8). Meta-analyses indicated that the ABOassociation was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared to antibody-positive (functional assay-negative) controls than to antibody-negative controls. Sequencing and fine-mapping of ABOdemonstrated that rs8176719 was the causal 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.