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Large deletions in the gene predict immune tolerance induction failure in people with severe hemophilia A.

Research and practice in thrombosis and haemostasis

Authors: Ilja Oomen, Amal Abdi, Linda Broer, Ricardo M Camelo, Fábia M R A Callado, Luany E M Carvalho, Ilenia L Calcaterra, Manuel Carcao, Giancarlo Castaman, Jeroen C J Eikenboom, Kathelijn Fischer, Vivian K B Franco, Judy Geissler, Taco W Kuijpers, Frank W G Leebeek, David Lillicrap, Cláudia S Lorenzato, Maria Elisa Mancuso, Davide Matino, Matteo N D Di Minno, Aomei Mo, Alex B Mohseny, Sietse Q Nagelkerke, Johannes Oldenburg, Suely Meireles Rezende, Georges-Etienne Rivard, Natalia Rydz, Saskia E M Schols, Michael W T Tanck, Jan Voorberg, Karin Fijnvandraat, Samantha C Gouw

BACKGROUND: Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe hemophilia A (SHA). Successful ITI restores factor VIII (FVIII) tolerance. ITI is demanding and successful in approximately 70% of people.

OBJECTIVES: Identifying predictors of ITI outcome is essential to guide clinical decision making. We aimed to identify genetic predictors of ITI success in people with SHA and inhibitors who underwent ITI.

METHODS: This observational multicenter study included people with SHA who underwent ITI, between 2015 and 2023. Clinical and patient data, including FVIII gene () mutation type, and DNA samples were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. By employing a global screening array, the associations between ITI success and genotype and 216 candidate predictors, including single nucleotide polymorphisms and human leukocyte antigen variants, CA dinucleotide short tandem repeat polymorphisms in the promoter region, and gene locus variations, were analyzed.

RESULTS: Of 204 participants, 147 (72.1%) achieved ITI success. The majority (52.0%) of participants had intron 22 inversion. None of the candidate single nucleotide polymorphisms/human leukocyte antigen variants, CA dinucleotide short tandem repeats, or gene locus variations were associated with ITI success. large deletions were negatively associated with ITI success (odds ratio, 0.15; 95% CI, 0.04-0.51; = .002).

CONCLUSION: Our study of 204 people with SHA identified large deletions as a predictor of ITI failure. Pooling cohorts may allow the identification of additional genetic predictors of ITI success in the future.

© 2025 The Author(s).

PMID: 41246453

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