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

被引:173
作者
Astermark, Jan [1 ]
Oldenburg, Johannes
Carlson, Joyce
Pavlova, Anna
Kavakli, Kaan
Berntorp, Erik
Lefvert, Ann-Kari
机构
[1] Malmo Univ Hosp, Dept Coagulat Disorders, SE-20502 Malmo, Sweden
[2] Malmo Univ Hosp, Dept Coagulat Disorders & Clin Chem, SE-20502 Malmo, Sweden
[3] Univ Clin Frankfurt, Inst Transfus Med & Immunohaematol, Frankfurt, Germany
[4] Univ Clin Bonn, Inst Expt Haematol & Transfus Med, Bonn, Germany
[5] Ege Univ Hosp, Dept Pediat Hematol, Izmir, Turkey
[6] Karolinska Inst, Immunol Res Lab, Ctr Mol Med, Stockholm, Sweden
[7] Karolinska Inst, Dept Med, Stockholm, Sweden
关键词
D O I
10.1182/blood-2006-05-024711
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:3739 / 3745
页数:7
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