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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3167-3172.
Prepublished online as a Blood First Edition Paper on December 27, 2005; DOI 10.1182/blood-2005-09-3918.
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Submitted September 30, 2005
Accepted December 1, 2005
Polymorphisms in the IL-10 but not in the IL-1 and IL-4 genes are associated with inhibitor development in patients with hemophilia A
Jan Astermark*, Johannes Oldenburg, Anna Pavlova, Erik Berntorp, and Ann-Kari Lefvert
Dept for Coagulation Disorders, Malmo University Hospital, Malmo, Sweden
Institute of Transfusion Medicine and Immunohaematology, University Clinic, Frankfurt, Germany; Institute of Experimental Haematology and Transfusion Medicine, Univeristy Clinic Bonn, Bonn, Germany
Institute of Transfusion Medicine and Immunohaematology, University Clinic, Frankfurt, Germany
Immunological Research Laboratory, Center for Molecular Medicine and Department of Medicine, Karolinska Institute, Stockholm, Sweden
* Corresponding author; email: jan.astermark{at}med.lu.se.
The aim of the Malmo International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. The factor VIII gene mutations and genetic polymorphisms of the IL-1 , IL-4 and IL-10 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 severe, 26 moderate and 14 mild) in 78 unrelated families with hemophilia A. Seventy-seven patients (47.0%) belonging to 54 families had a history of inhibitors (57 high-responding, 20 low-responding). Inversions were found in 36 of the families (75 patients). There was no association between development of inhibitor and the IL-1 Taq I RFLP alleles in exon 5, or the -590 C/T SNP in the promoter region of IL-4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL-10.G, located in the promoter region of the IL-10 gene, and development of inhibitor (OR 4.4, 95% CI 2.1-9.5; p< 0.001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL-10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development.
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