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Ferrata Storti Foundation, Haematologica, 10(98), p. 1650-1655

DOI: 10.3324/haematol.2013.084665

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Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Induction of heme oxygenase-1 (HO-1), a stress inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In human, HO-1 expression is modulated by polymorphisms in the promoter of the HO-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitor within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT)n polymorphism and single nucleotide polymorphisms located at 1135 and 413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate a higher frequency in inhibitor-positive patients of alleles with large (GT)n repeats (L: n≥30), that are associated with a lesser HO-1 expression [odds ratio (OR) 2.31; 95% CI 1.46-3.66, p<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) [OR 2.21, 95% CI 1.30-3.76, p<0.01]. To our knowledge, this is the first association between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development.