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

Astermark, Jan LU ; Oldenburg, Johannes; Carlson, Joyce LU ; Pavlova, Anna; Kavakli, Kaan; Berntorp, Erik LU and Lefvert, Ann-Kari (2006) In Blood 108(12). p.3739-3745
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
108
issue
12
pages
3739 - 3745
publisher
American Society of Hematology
external identifiers
  • wos:000242309800025
  • scopus:33845239946
ISSN
1528-0020
DOI
10.1182/blood-2006-05-024711
language
English
LU publication?
yes
id
073e42b4-0679-437c-b481-85afddf0433d (old id 159967)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16926287&dopt=Abstract
date added to LUP
2007-07-11 14:30:46
date last changed
2019-04-10 01:37:09
@article{073e42b4-0679-437c-b481-85afddf0433d,
  abstract     = {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 &gt; T, -308G &gt; A, -238A &gt; G, and 670A &gt; 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 &lt; .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 &gt; A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.},
  author       = {Astermark, Jan and Oldenburg, Johannes and Carlson, Joyce and Pavlova, Anna and Kavakli, Kaan and Berntorp, Erik and Lefvert, Ann-Kari},
  issn         = {1528-0020},
  language     = {eng},
  number       = {12},
  pages        = {3739--3745},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.},
  url          = {http://dx.doi.org/10.1182/blood-2006-05-024711},
  volume       = {108},
  year         = {2006},
}