PMID- 28688202 OWN - NLM STAT- MEDLINE DCOM- 20180521 LR - 20240216 IS - 1875-9114 (Electronic) IS - 0277-0008 (Print) IS - 0277-0008 (Linking) VI - 37 IP - 9 DP - 2017 Sep TI - Influence of Human Leukocyte Antigen (HLA) Alleles and Killer Cell Immunoglobulin-Like Receptors (KIR) Types on Heparin-Induced Thrombocytopenia (HIT). PG - 1164-1171 LID - 10.1002/phar.1983 [doi] AB - 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=2.1x10(-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. CI - (c) 2017 Pharmacotherapy Publications, Inc. FAU - Karnes, Jason H AU - Karnes JH AD - Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona. AD - Sarver Heart Center, Tucson, Arizona. FAU - Shaffer, Christian M AU - Shaffer CM AD - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. FAU - Cronin, Robert AU - Cronin R AD - Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Bastarache, Lisa AU - Bastarache L AD - Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Gaudieri, Silvana AU - Gaudieri S AD - School of Anatomy, Physiology and Human Biology, University of Western Australia, Nedlands, Western Australia, Australia. AD - Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. AD - Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia. FAU - James, Ian AU - James I AD - Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia. FAU - Pavlos, Rebecca AU - Pavlos R AD - Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia. FAU - Steiner, Heidi E AU - Steiner HE AD - Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona. FAU - Mosley, Jonathan D AU - Mosley JD AD - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. FAU - Mallal, Simon AU - Mallal S AD - Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. AD - Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia. AD - Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Denny, Joshua C AU - Denny JC AD - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. AD - Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Phillips, Elizabeth J AU - Phillips EJ AD - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. AD - Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Roden, Dan M AU - Roden DM AD - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. AD - Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee. AD - Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee. LA - eng GR - UL1 TR000445/TR/NCATS NIH HHS/United States GR - T32 GM007569/GM/NIGMS NIH HHS/United States GR - U19 HL065962/HL/NHLBI NIH HHS/United States GR - U01 HG004603/HG/NHGRI NIH HHS/United States GR - U01 HG008672/HG/NHGRI NIH HHS/United States GR - 16FTF30130005/AHA/American Heart Association-American Stroke Association/United States GR - RC2 GM092618/GM/NIGMS NIH HHS/United States GR - P50 GM115305/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20170904 PL - United States TA - Pharmacotherapy JT - Pharmacotherapy JID - 8111305 RN - 0 (Anticoagulants) RN - 0 (HLA Antigens) RN - 0 (Receptors, KIR) RN - 9005-49-6 (Heparin) SB - IM MH - Adult MH - Aged MH - *Alleles MH - Anticoagulants/adverse effects MH - Case-Control Studies MH - Databases, Nucleic Acid MH - Female MH - HLA Antigens/*genetics MH - Heparin/*adverse effects MH - Humans MH - Male MH - Middle Aged MH - Receptors, KIR/*genetics MH - Thrombocytopenia/*chemically induced/*genetics PMC - PMC5600645 MID - NIHMS865033 OTO - NOTNLM OT - HLA OT - electronic health records OT - heparin-induced thrombocytopenia OT - immunogenetics OT - killer cell immunoglobulin-like receptor (KIR) OT - pharmacogenomics COIS- Disclosure of Conflicts of Interest The authors declare no competing financial interests. EDAT- 2017/07/09 06:00 MHDA- 2018/05/22 06:00 PMCR- 2018/09/04 CRDT- 2017/07/09 06:00 PHST- 2017/07/09 06:00 [pubmed] PHST- 2018/05/22 06:00 [medline] PHST- 2017/07/09 06:00 [entrez] PHST- 2018/09/04 00:00 [pmc-release] AID - 10.1002/phar.1983 [doi] PST - ppublish SO - Pharmacotherapy. 2017 Sep;37(9):1164-1171. doi: 10.1002/phar.1983. Epub 2017 Sep 4.