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Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A

Pavlova, A.; Delev, D.; Lacroix-Desmazes, S.; Schwaab, R.; Mende, M.; Fimmers, R.; Astermark, Jan LU and Oldenburg, J. (2009) In Journal of Thrombosis and Haemostasis 7(12). p.2006-2015
Abstract
Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF-alpha, the A allele of the -308G > A polymorphism was found with... (More)
Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF-alpha, the A allele of the -308G > A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL-10, the -1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high-TNF-alpha/high-IL-10 producers, as compared with 3% of non-inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA-4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the -308G > A polymorphism in TNF-alpha and -1082A > G in IL-10 in inhibitor patients confirmed the earlier published data. The CT60 single-nucleotide polymorphism in CTLA-4 is of apparently less importance. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
inhibitors, IL-10, HLA, CTLA-4, hemophilia A, TNF-alpha
in
Journal of Thrombosis and Haemostasis
volume
7
issue
12
pages
2006 - 2015
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000272130500008
  • scopus:77449101167
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2009.03636.x
language
English
LU publication?
yes
id
d268d00f-0257-4fe2-aa72-ef6129f6f5bb (old id 1517663)
date added to LUP
2010-01-04 15:41:42
date last changed
2017-12-10 03:51:07
@article{d268d00f-0257-4fe2-aa72-ef6129f6f5bb,
  abstract     = {Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P &lt; 0.05]. In TNF-alpha, the A allele of the -308G &gt; A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL-10, the -1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high-TNF-alpha/high-IL-10 producers, as compared with 3% of non-inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA-4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the -308G &gt; A polymorphism in TNF-alpha and -1082A &gt; G in IL-10 in inhibitor patients confirmed the earlier published data. The CT60 single-nucleotide polymorphism in CTLA-4 is of apparently less importance.},
  author       = {Pavlova, A. and Delev, D. and Lacroix-Desmazes, S. and Schwaab, R. and Mende, M. and Fimmers, R. and Astermark, Jan and Oldenburg, J.},
  issn         = {1538-7933},
  keyword      = {inhibitors,IL-10,HLA,CTLA-4,hemophilia A,TNF-alpha},
  language     = {eng},
  number       = {12},
  pages        = {2006--2015},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2009.03636.x},
  volume       = {7},
  year         = {2009},
}