Influence of Human Leukocyte Antigen (HLA) Alleles and Killer Cell Immunoglobulin‐Like Receptors (KIR) Types on Heparin‐Induced Thrombocytopenia (HIT)

Abstract

Objectives Variation in human leukocyte antigen (HLA) genes is now used to prevent immune-mediated adverse drug reactions. Combinations of HLA alleles and killer cell immunoglobulin-like receptors (KIR) are associated with multiple autoimmune diseases and infections. Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin. The objective of this study is to evaluate the association of HLA alleles and KIR types, alone or in the presence of different HLA ligands, with HIT. Methods We identified HIT cases and heparin-exposed controls in BioVU, an electronic health record coupled to a DNA biobank. We performed HLA sequencing and imputed KIR types from Illumina® OMNI-Quad data. We determined odds ratios (ORs) for HLA alleles and KIR types and HLA*KIR interactions using conditional logistic regressions in the overall population and by race/ethnicity. Analysis was restricted to KIR types and HLA alleles with a frequency greater than 0.01. P values for HLA and KIR association were corrected using a false discovery rate (FDR) q<0.05 and HLA*KIR interactions were considered significant at p<0.05. Results We identified 65 HIT cases and 350 matched controls. We observed no statistical differences in baseline characteristics between cases and controls. The HLA-DRB3*01:01 allele was significantly associated with HIT in the overall population (OR 2.81[1.57–5.02], p=2.1x10−4, q=0.02) and in individuals with European ancestry, independent of other alleles. No KIR types were associated with HIT, although we observed a significant interaction between KIR2DS5 and the HLA-C1 KIR binding group (p=0.03). Conclusions We identify the HLA-DRB3*01:01 allele as a potential risk factor for HIT. This class II HLA gene and allele represent biologically plausible candidates for influencing HIT pathogenesis. We found limited evidence of the role of KIR types in HIT pathogenesis. Replication and further study of the HLA-DRB3*01:01 association is necessary.

Pathogenesis of heparin-induced thrombocytopenia

“…Other supporting data come from findings of a restricted T cell repertoire in patients with HIT 42,43 and the requirement for T cells in the murine HIT immune response. [44][45][46] Recent genome wide association (GWAS) studies, though involving small numbers of patients, identified several candidate genes, 47,48 including an HLA-DRB3*01:01 allele associated with a greater risk of developing HIT 49 ; these findings will require validation in larger cohorts.…”

A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2

“…The HLA-types DRB1*11 and DQB1*03:01 are associated with an increased risk of thrombocytopenic thrombotic purpura, and DRB1*11 is tightly linked to DRB3*01:01, identified as a potential risk factor for the development of HIT. 20 …”

Onset of type 1 diabetes mellitus and heparin‐induced thrombocytopenia in a patient with Basedow's disease and idiopathic thrombocytopenic purpura: Novel combination as autoimmune polyglandular syndrome

“…Anti‐HIT antibody is an antibody against the complex of platelet factor 4 and heparin, which is thought to lead to the onset of HIT. Very recently, the HLA‐DRB3 *01:01 allele was identified as a potential risk factor for HIT in people of European ancestry4. Although we did not check this allele, this allele might have been associated with the onset of HIT in this patient.…”