TY - JOUR
T1 - ABO O blood group as a risk factor for platelet reactivity in heparin-induced thrombocytopenia
AU - Karnes, Jason H.
AU - Rollin, Jerome
AU - Giles, Jason B.
AU - Martinez, Kiana L.
AU - Steiner, Heidi E.
AU - Shaffer, Christian M.
AU - Momozawa, Yukihide
AU - Inai, Chihiro
AU - Bombin, Andrei
AU - Shi, Mingjian
AU - Mosley, Jonathan D.
AU - Stanaway, Ian
AU - Selleng, Kathleen
AU - Thiele, Thomas
AU - Mushiroda, Taisei
AU - Pouplard, Claire
AU - Heddle, Nancy M.
AU - Kubo, Michiaki
AU - Phillips, Elizabeth J.
AU - Warkentin, Theodore E.
AU - Gruel, Yves
AU - Greinacher, Andreas
AU - Roden, Dan M.
N1 - Funding Information:
Genome-wide data and ABO sequence data were provided by the Pharmacogenomics Research Network (PGRN)-RIKEN Collaborative. This research is funded by the National Institutes of Health's (NIH) National Heart, Lung, and Blood Institute (NHLBI) under awards K01HL143137 (J.H.K.), R01HL156993 (J.H.K.), R01HL158686 (J.H.K.), and U19 HL065962 (D.M.R.), the National Institute of General Medical Sciences (NIGMS) under award P50GM115305 (D.M.R.), and the National Institute of Environmental Health Sciences (NIEHS) under award T32 ES007091 (J.B.G.). Acquisition of the replication cohort from the University of Tours with the independent replication population was supported by the IRTH (Institut pour la Recherche sur la Thrombose et l'Hémostase) and by a PHRC grant (PHRN09-YG/FRIGTIH). The study was supported by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) Project Number 374031971–TRR240 (A.G.). Dataset(s) obtained from Vanderbilt University Medical Center's BioVU are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711. Additional funding sources are listed at https://victr.vumc.org/biovu-funding .
Funding Information:
The authors thank the staff of the Laboratory for Genotyping Development, RIKEN Center for the Integrative Medical Sciences. They are grateful to Ulrike Strobel, Carmen Freyer, Katrin Stein, Ines Warnig, Ricarda Raschke, and Jessica Fuhrmann for excellent technical support in performing all HIT assays in the discovery cohort. Genome-wide data and ABO sequence data were provided by the Pharmacogenomics Research Network (PGRN)-RIKEN Collaborative. This research is funded by the National Institutes of Health's (NIH) National Heart, Lung, and Blood Institute (NHLBI) under awards K01HL143137 (J.H.K.), R01HL156993 (J.H.K.), R01HL158686 (J.H.K.), and U19 HL065962 (D.M.R.), the National Institute of General Medical Sciences (NIGMS) under award P50GM115305 (D.M.R.), and the National Institute of Environmental Health Sciences (NIEHS) under award T32 ES007091 (J.B.G.). Acquisition of the replication cohort from the University of Tours with the independent replication population was supported by the IRTH (Institut pour la Recherche sur la Thrombose et l'Hémostase) and by a PHRC grant (PHRN09-YG/FRIGTIH). The study was supported by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) Project Number 374031971–TRR240 (A.G.). Dataset(s) obtained from Vanderbilt University Medical Center's BioVU are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711. Additional funding sources are listed at https://victr.vumc.org/biovu-funding.
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/7/21
Y1 - 2022/7/21
N2 - Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10−8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10−209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P =.034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10−9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P =.0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10−8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.
AB - Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10−8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10−209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P =.034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10−9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P =.0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10−8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.
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U2 - 10.1182/blood.2021014240
DO - 10.1182/blood.2021014240
M3 - Article
C2 - 35377938
AN - SCOPUS:85134734010
SN - 0006-4971
VL - 140
SP - 274
EP - 284
JO - Blood
JF - Blood
IS - 3
ER -