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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
; ; ; ; ; ; and
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
Wiley-Blackwell
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
2016-04-01 12:18:14
date last changed
2022-05-07 00:45:21
@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}},
  keywords     = {{inhibitors; IL-10; HLA; CTLA-4; hemophilia A; TNF-alpha}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2006--2015}},
  publisher    = {{Wiley-Blackwell}},
  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}},
  doi          = {{10.1111/j.1538-7836.2009.03636.x}},
  volume       = {{7}},
  year         = {{2009}},
}