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

• Published in: Journal of thrombosis and haemostasis Vol. 7; no. 12; pp. 2006 - 2015
• Main Authors: PAVLOVA, A., DELEV, D., LACROIX‐DESMAZES, S., SCHWAAB, R., MENDE, M., FIMMERS, R., ASTERMARK, J., OLDENBURG, J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2009
• Subjects: Antigens, CD - genetics; Autoantibodies - biosynthesis; Autoantibodies - genetics; Cardiac and Cardiovascular Systems; Clinical Medicine; CTLA-4; CTLA-4 Antigen; Gene Frequency; Genes, MHC Class II - genetics; hemophilia A; Hemophilia A - epidemiology; Hemophilia A - genetics; Hemophilia A - immunology; hemophilia A; HLA; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Humans; IL-10; inhibitors; Interleukin-10 - genetics; Kardiologi; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Polymorphism, Genetic - immunology; TNF-alpha; TNF‐α; Tumor Necrosis Factor-alpha - genetics
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2009.03636.x

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‐α (TNF‐α) 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‐α, 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‐α/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‐α 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.