title: Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter.
abstract: Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-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 inhibitors 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 that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 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%) (odds ratio 2.21, 95% confidence interval 1.30-3.76; P<0.01). To our knowledge, this is the first association identified 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.
authors.affiliation: Sebastien.Lacroix-Desmazes@crc.jussieu.fr.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Repessé
authors.forename: Ivan
authors.initials: I
authors.lastname: Peyron
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Dimitrov
authors.forename: Suryasarathi
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Elika Farrokhi
authors.initials: EF
authors.lastname: Moshai
authors.forename: Catherine
authors.initials: C
authors.lastname: Costa
authors.forename: Annie
authors.initials: A
authors.lastname: Borel-Derlon
authors.forename: Benoit
authors.initials: B
authors.lastname: Guillet
authors.forename: Roseline
authors.initials: R
authors.lastname: D'Oiron
authors.forename: Achille
authors.initials: A
authors.lastname: Aouba
authors.forename: Chantal
authors.initials: C
authors.lastname: Rothschild
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlova
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000906:Antibodies / Q000097:blood; D016022:Case-Control Studies; D005169:Factor VIII / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D000906:Antibodies; D005169:Factor VIII; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1