Submitted May 22, 2006
Accepted July 22, 2006
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, and Ann-Kari Lefvert
Department for Coagulation Disorders, Malmo University Hospital, Sweden
Institute of Experimental Haematology and Transfusion Medicine
Clinical Chemistry, Malmo University Hospital, Sweden
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
Department of Pediatric Hematology, Ege University Hospital, Izimir, Turkey
Institute of Transfusion Medicine and Immunohaematology, University Clinic, Frankfurt, Germany
Immunological Research Laboratory, Center for Molecular Medicine, Karolinska Institute, Stockholm
* Corresponding author; email: jan.astermark{at}med.lu.se.
The HLA class I/II alleles and the tumor necrosis factor
alpha (TNFA) locus are closely linked in the MHC complex.
We have characterized the causative factor VIII mutation,
HLA alleles as well as four 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=0.008). 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<0.001), and with
inversions (n=75; OR 11.8, 95% CI 1.3-105.1; p=0.013).
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.
