Large deletions in the F8 gene predict immune tolerance induction failure in people with severe hemophilia A

TL;DR

Large deletions in the F8 gene are linked to a lower chance of successful immune tolerance induction in people with severe hemophilia A.

Contribution

This study identifies F8 large deletions as a novel genetic predictor of immune tolerance induction failure in hemophilia A patients.

Findings

F8 large deletions were negatively associated with immune tolerance induction success (odds ratio, 0.15).

No single nucleotide polymorphisms or HLA variants were found to predict ITI success.

The study included 204 participants, with 72.1% achieving successful immune tolerance induction.

Abstract

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.

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 FVIII 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. By employing a global screening array, the associations between ITI success and F8 genotype and 216 candidate predictors, including single nucleotide polymorphisms and human leukocyte antigen variants, CA dinucleotide short tandem repeat polymorphisms in the IL10 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 single nucleotide polymorphisms/human leukocyte antigen variants, IL10 CA dinucleotide short tandem repeats, or FCGR2/3 gene locus variations were associated with ITI success. F8 large deletions were negatively associated with ITI success (odds ratio, 0.15; 95% CI, 0.04-0.51; P = .002).

Our study of 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.

•Identifying genetic predictors of immune tolerance induction success may guide shared decision making.•In 204 people with severe hemophilia A and inhibitors, F8 large deletions were associated with immune tolerance induction failure.

Identifying genetic predictors of immune tolerance induction success may guide shared decision making.

In 204 people with severe hemophilia A and inhibitors, F8 large deletions were associated with immune tolerance induction failure.

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