An immunological reaction to platelet factor 4 (PF4)/heparin complexes can cause a dangerous side effect called heparin-induced thrombocytopenia (HIT). In a large discovery cohort of patients divided into 3 groups, researchers conducted a genome-wide association study (GWAS) with a positive functional assay as the outcome.
These groups were: functional assay-positive cases (n=1,269), antibody-positive (functional assay-negative) controls (n=1,131), and antibody-negative controls (n=1,766). In a replication cohort of functional assay-confirmed HIT patients (n=177), antibody-positive (function assay-negative) controls (n=258), and antibody-negative controls (n=351), significant relationships (α=5×10−8) were analyzed.
They found a significant correlation between rising PF4/heparin immunoglobulin-G (IgG) levels and positive functional assays (odds ratio [OR], 16.53; 95% CI, 13.83-19.74; P=1.51×10−209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P=.034). In the discovery cohort (frequency=0.41; OR, 0.751; 95% CI, 0.682-0.828; P=7.80×10−9) and replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P=.0367), the rs8176719 C insertion variation in ABO was strongly linked with positive functional test status. The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, showing that the O blood group and the rs8176719 C deletion were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P=3.09×10−8). The meta-analyses showed that the ABO association 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 when antibody-negative controls were compared to functional assay-positive cases. ABO sequencing and fine-mapping showed that the causative single nucleotide polymorphism (SNP) was rs8176719.
The study’s findings explained the biology behind HIT pathogenesis, with implications for prediction and significant consequences for related disorders including vaccine-induced thrombotic thrombocytopenia.