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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3739-3745.
Prepublished online as a Blood First Edition Paper on August 22, 2006; DOI 10.1182/blood-2006-05-024711.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A
Jan Astermark,
Johannes Oldenburg,
Joyce Carlson,
Anna Pavlova,
Kaan Kavakli,
Erik Berntorp,
Ann-Kari Lefvert, and
the MIBS Study Group
From the Department for Coagulation Disorders and Clinical Chemistry, Malmö University Hospital, Malmö, Sweden; Institute of Transfusion Medicine and Immunohaematology, University Clinic, Frankfurt, Germany; Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany; Department of Pediatric Hematology, Ege University Hospital, Izmir, Turkey; and Immunological Research Laboratory, Center for Molecular Medicine and Department of Medicine, Karolinska Institute, Stockholm, Sweden.
The HLA class I/II alleles and the tumor necrosis factor (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (827C>T, 308G>A, 238A>G, and 670A>G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmö International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA 308 A/A genotype within this haplotype compared with 39.7% for TNFA 308 G/G patients and 46.9% for TNFA 308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the 308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P < .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P = .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA 308G>A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.

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