PMID- 19817985
OWN - NLM
STAT- MEDLINE
DCOM- 20100302
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 7
IP  - 12
DP  - 2009 Dec
TI  - 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.
PG  - 2006-2015
LID - 10.1111/j.1538-7836.2009.03636.x [doi]
AB  - 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-alp[ha, 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.
FAU - Pavlova, A
AU  - Pavlova A
AD  - Experimental Heamatology and Transfusion Medicine, University of Clinic Bonn, 
      Sigmund- Freud-Str. 25, Germany
FAU - Delev, D
AU  - Delev D
FAU - Lacroix-Desmazes, S
AU  - Lacroix-Desmazes S
FAU - Schwaab, R
AU  - Schwaab R
FAU - Mende, M
AU  - Mende M
FAU - Fimmers, R
AU  - Fimmers R
FAU - Astermark, J
AU  - Astermark J
FAU - Oldenburg, J
AU  - Oldenburg J
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Antigens, CD)
RN  - 0 (Autoantibodies)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (CTLA4 protein, human)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*15 antigen)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
SB  - IM
MH  - Antigens, CD/*genetics
MH  - Autoantibodies/*biosynthesis/genetics
MH  - CTLA-4 Antigen
MH  - Gene Frequency
MH  - Genes, MHC Class II/*genetics
MH  - HLA-DQ Antigens/genetics
MH  - HLA-DQ beta-Chains
MH  - HLA-DR Antigens/genetics
MH  - HLA-DRB1 Chains
MH  - Hemophilia A/epidemiology/genetics/*immunology
MH  - Humans
MH  - Interleukin-10/*genetics
MH  - Polymorphism, Genetic/*immunology
MH  - Tumor Necrosis Factor-alpha/*genetics
EDAT- 2009/10/13 06:00
MHDA- 2010/03/03 06:00
CRDT- 2009/10/13 06:00
PHST- 2009/10/13 06:00 [entrez]
PHST- 2009/10/13 06:00 [pubmed]
PHST- 2010/03/03 06:00 [medline]
AID - S1538-7836(22)13431-8 [pii]
AID - 10.1111/j.1538-7836.2009.03636.x [doi]
PST - ppublish
SO  - J Thromb Haemost. 2009 Dec;7(12):2006-2015. doi: 
      10.1111/j.1538-7836.2009.03636.x.