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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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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A
Jan Astermark,
Johannes Oldenburg,
Anna Pavlova,
Erik Berntorp,
Ann-Kari Lefvert, for the MIBS Study Group
From the Department for Coagulation Disorders, Malmö University Hospital, Malmö, Sweden; Institute of Transfusion Medicine and Immunohaematology, University Clinic, Frankfurt; Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany; and Immunological Research Laboratory, Center for Molecular Medicine and Department of Medicine, Karolinska Institute, Stockholm, Sweden.
The aim of the Malmö International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. Factor VIII gene mutations and genetic polymorphisms of the IL1beta, IL4, and IL10 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 with severe, 26 with moderate, and 14 with mild disease) in 78 unrelated families with hemophilia A. Seventy-seven (47%) patients in 54 families had a history of inhibitors (57 high responding, 20 low responding). Inversions were found in 36 families (75 patients). There was no association between the development of inhibitor and the IL1beta Taq I RFLP alleles in exon 5 or the –590 C/T single nucleotide polymorphism (SNP) in the promoter region of IL4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL10G, located in the promoter region of the IL10 gene, and the development of inhibitor (odds ratio [OR], 4.4; 95% confidence interval [95% CI], 2.1-9.5; P < .001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development.
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