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Vol. 46. Núm. S4.
HEMO 2024
Páginas S564 (outubro 2024)
Vol. 46. Núm. S4.
HEMO 2024
Páginas S564 (outubro 2024)
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LARGE DELETIONS IN THE F8 GENE PREDICT IMMUNE TOLERANCE INDUCTION FAILURE IN PEOPLE WITH SEVERE HEMOPHILIA A
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I Oomena,b, A Abdia, L Broerc, RM Camelod,e, FMRA Calladof, LEM Carvalhog, IL Calcaterrah, M Carcaoi, G Castamanj, JCJ Eikenboome, K Fischerk, VKB Francol, J Geisslerb, TW Kuijpersa,b, FWG Leebeekc, D Lillicrapm, CS Lorenzaton, ME Mancusoo, D Matinop, MND Di Minnoh..., A Mom, AB Mohsenye, SQ Nagelkerkea,b, J Oldenburgq, SM Rezended, K Fijnvandraata, S Gouwa,e, International GO-ITI Steering Group Ver más
a Amsterdam University Medical Center, Amsterdam, The Netherlands
b Sanquin Research, Amsterdam, The Netherlands
c Erasmus University Medical Center, Rotterdam, The Netherlands
d Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
e Leiden University Medical Center, Leiden, The Netherlands
f Fundação de Hematologia e Hemoterapia de Pernambuco (HEMOPE), Recife, PE, Brazil
g Centro de Hematologia e Hemoterapia do Ceará (HEMOCE), Fortaleza, CE, Brazil
h Federico II University, Naples, Italy
i Hospital for Sick Children, Toronto, Canada
j Careggi University Hospital, Florence, Italy
k University Medical Center Utrecht, Utrecht, the Netherlands
l Centro de Hematologia e Hemoterapia de Santa Catarina (HEMOSC), Florianópolis, SC, Brazil
m Queen's University, Kingston, Canada
n Centro de Hematologia e Hemoterapia do Paraná (HEMEPAR), Curitiba, PR, Brazil
o IRCCS Humanitas Research Hospital, Milan, Italy
p McMaster University, Hamilton, Canada
q University of Bonn, Bonn, Germany
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Vol. 46. Núm S4

HEMO 2024

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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. Therefore, 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. This observational multicenter study included people with SHA who underwent ITI, between 2015 and 2023. Clinical and patient data including factor VIII gene (F8) mutation type and DNA samples were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. The associations between ITI success and F8 genotype and 216 candidate predictors including single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA)-variants employing a global screening array (GSA), CA dinucleotide Short Tandem Repeat (STR) polymorphisms in the Interleukin (IL)-10 promoter region, and FCGR2/3 gene locus variations were analyzed. Of 204 participants, 147 (72.1%) achieved ITI success. The majority (52.0%) of participants had F8 intron 22 inversion. None of the candidate SNPs/HLA-variants, IL-10 CA dinucleotide STR, or FCGR2/3 gene locus variations were associated with ITI success. F8 large deletions were negatively associated with ITI success (OR = 0.15, 95% CI 0.04‒0.51, p = 0.002). Our study including 204 people with SHA identified F8 large deletions as a predictor of ITI failure. Pooling cohorts may allow the identification of additional genetic predictors of ITI success in the future.

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Idiomas
Hematology, Transfusion and Cell Therapy
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