-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

842 Genome-Wide Association Study Identifies Variation in ABO As Risk Factor for Platelet Reactivity in Heparin-Induced Thrombocytopenia

Program: Oral and Poster Abstracts
Session: 311. Disorders of Platelet Number or Function: Poster I
Hematology Disease Topics & Pathways:
Adult, Diseases, Bleeding and Clotting, HIT, Technology and Procedures, Study Population, NGS
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Jason B Giles1*, Jérôme Rollin, PhD2*, Christian M Shaffer3*, Heidi E Steiner1*, Yukihide Momozawa, DVM, Ph.D4*, Ian Stanaway, PhD5*, Taisei Mushiroda6*, Claire Pouplard, PharmD, PhD2*, Nancy Heddle, MSc7, Michiaki Kubo, MD, Ph.D8*, Elizabeth Phillips, MD3*, Theodore E. Warkentin, MD9, Yves Gruel, MD, PhD10, Andreas Greinacher, MD11, Dan Roden, MD3* and Jason Karnes, PhD, PharmD1

1University of Arizona, Tucson, AZ
2Department of Hematology-Hemostasis, University Hospital of Tours, Tours, France
3Vanderbilt University Medical Center, Nashville, TN
4Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
5University of Washington, Seattle, WA
6RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
7Department of Medicine, McMaster University, Hamilton, ON, Canada
8Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
9McMaster University, Hamilton, ON, Canada
10Department of Hematology-Hemostasis, University Hospital of Tours, Chambray-Lès-Tours, France
11Institute for Immunology & Transfusion Ernst-Moritz-Arndt-University, Greifswald, Germany

Background: Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. Genome-wide association studies (GWAS) have the potential to identify genetic risk factors and generate insights into biological mechanisms of adverse drug reactions. However, published HIT GWAS are underpowered and do not include confirmation of HIT using functional assays. We aimed to identify genetic associations with HIT using a GWAS approach in two European ancestry populations tested for functional assay and PF4/heparin antibody levels.

Methods: We performed a GWAS with positive functional assay as the outcome in a large discovery cohort of patients, including heparin-induced platelet aggregation (HIPA) positive cases (n=1243), antibody positive but functional assay negative controls (n=1091), and antibody negative controls (n=1718). Logistic regressions were adjusted for age, gender, and first two principal components. Significant associations from the discovery cohort (alpha=5.00x10-8) were then investigated in a replication cohort of serotonin-release assay (SRA)-confirmed HIT cases (n=173), antibody positive controls (n=125), and antibody negative controls (n=488). All patients were genotyped with the HumanOmniExpressExome BeadChip, including 9,065,510 variants after imputation and quality control. Genes near significantly associated loci were resequenced.

Results: In the discovery cohort, a genome-wide significant association was observed between common variation in the ABO gene and HIPA positive status (rs505922 odds ratio 0.738 [0.668-0.816], p=2.813x10-9). This variant was also significantly associated with SRA-confirmed HIT in the replication cohort (odds ratio 0.392 [0.172-0.891], p=0.025). Meta-analysis indicated strong association of ABO variation with positive functional assay (Figure 1). Sequencing and fine-mapping of the ABO locus indicated this effect was driven by ABO blood groups, with the O blood group being a risk factor for HIT (odds ratio 1.42 [1.25-1.61], p=6.11x10-8).

Conclusions: We identify common variation in ABO as a risk factor for platelet reactivity and HIT. Strong association of ABO variation may have important implications for prediction and understanding of HIT pathogenesis.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH