HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A

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. (Blood. 2006;108:3739-3745)