Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A


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ASTERMARK J., OLDENBURG J., CARLSON J., PAVLOVA A., Kavakli K. , BERNTORP E., ...Daha Fazla

BLOOD, cilt.108, ss.3739-3745, 2006 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 108 Konu: 12
  • Basım Tarihi: 2006
  • Doi Numarası: 10.1182/blood-2006-05-024711
  • Dergi Adı: BLOOD
  • Sayfa Sayıları: ss.3739-3745

Özet

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 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 Malmo 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 39.70/6 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.