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.
abstract: BACKGROUND
  Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein.
  
  
  METHODS
  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.
authors.affiliation: Experimental Heamatology and Transfusion Medicine, University of Clinic Bonn, Sigmund- Freud-Str. 25, Germany
authors.forename: A
authors.initials: A
authors.lastname: Pavlova
authors.forename: D
authors.initials: D
authors.lastname: Delev
authors.forename: S
authors.initials: S
authors.lastname: Lacroix-Desmazes
authors.forename: R
authors.initials: R
authors.lastname: Schwaab
authors.forename: M
authors.initials: M
authors.lastname: Mende
authors.forename: R
authors.initials: R
authors.lastname: Fimmers
authors.forename: J
authors.initials: J
authors.lastname: Astermark
authors.forename: J
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D001323:Autoantibodies / Q000096:biosynthesis* / Q000235:genetics; D060908:CTLA-4 Antigen; D005787:Gene Frequency; D005802:Genes, MHC Class II / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006467:Hemophilia A / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10