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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.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia AFrom 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
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
(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. 
