Influence of Human Leukocyte Antigen ( HLA ) Alleles and Killer Cell Immunoglobulin‐Like Receptors ( KIR ) Types on Heparin‐Induced Thrombocytopenia ( HIT )
Year: 2017
Type: article
Study design: Observational Study
Abstract: Heparin‐induced thrombocytopenia (HIT) is an unpredictable, life‐threatening, immune‐mediated reaction to heparin. 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. 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. HIT cases and heparin‐exposed controls were identified in BioVU, an electronic health record coupled to a DNA biobank. HLA sequencing and KIR type imputation using Illumina OMNI‐Quad data were performed. Odds ratios for HLA alleles and KIR types and HLA*KIR interactions using conditional logistic regressions were determined in the overall population and by race/ethnicity. Analysis was restricted to KIR types and HLA alleles with a frequency greater than 0.01. The p values for HLA and KIR association were corrected by using a false discovery rate q<0.05 and HLA*KIR interactions were considered significant at p<0.05. Sixty‐five HIT cases and 350 matched controls were identified. No statistical differences in baseline characteristics were observed between cases and controls. The HLA‐DRB3*01:01 allele was significantly associated with HIT in the overall population (odds ratio 2.81 [1.57–5.02], p=2.1×10−4, q=0.02) and in individuals with European ancestry, independent of other alleles. No KIR types were associated with HIT, although a significant interaction was observed between KIR2DS5 and the HLA‐C1 KIR binding group (p=0.03). The HLA‐DRB3*01:01 allele was identified 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.
DOI: 10.1002/phar.1983
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Heart Association, American College of Clinical Pharmacy Research Institute, Vanderbilt University, Vanderbilt University Medical Center, American College of Clinical Pharmacy, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences
Awards: Immunogenetics of Heparin-Induced Thrombocytopenia, G1435936284, Pharmacogenomics of Arrhythmia Therapy, G1846282300, G2103760183, Immunogenetics of Heparin-Induced Thrombocytopenia, G2683268942, G3272238124, Improving Prediction of Drug Action, G364208108, G3791753988, G3999073622, G4481548533, G510737083, G5679716143, VGER, the Vanderbilt Genome-Electronic Records Project, G6636911908, Delineating epidemiological and genetic factors associated with cardiac diastolic dysfunction, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, Vanderbilt Genome-Electronic Records Project, G7397460205, G7764234106, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G9000018720, G9000313436, Clinical Pharmacology Training Program
OpenAlex ID: W2733927229