Development of Inhibitory Antibodies to Therapeutic Factor VIII in Severe Hemophilia A Is Associated with Microsatellite Polymorphism in the HMOX1 promoter

Abstract 38

The occurrence of inhibitory anti-factor VIII (FVIII) antibodies is the major complication of replacement therapy in patients with hemophilia A. Heme oxygenase-1 (HO-1) is a stress inducible enzyme with anti-inflammatory activity. Induction of HO-1 in hemophilic mice reduces the immunogenicity of therapeutic FVIII. Interestingly, polymorphisms in the promoter of the HO-1-encoding gene (HMOX1) modulate the expression of HO-1.

We investigated the relationship between polymorphisms in the promoter of HMOX1 in severe hemophilia A patients and the development of FVIII inhibitors.

We analyzed 362 patients with severe hemophilia A involving 99 patients with FVIII inhibitors and 263 patients who did not develop inhibitor within the first 150 cumulative exposure days to therapeutic FVIII. Direct sequencing and DNA fragment analysis were used to study the variable (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 and genotypes, and the development of inhibitors.

Our results demonstrate a higher frequency of alleles with large (GT)_n repeat (n≥30, L, associated with a lesser expression of HO-1) in inhibitor-positive patients [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% vs 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. Modulating the endogenous anti-inflammatory machinery of hemophilia A patients appears as a plausible therapeutic option for reducing the risk of inhibitor development.