Impact of polymorphisms in genes involved in autoimmune disease on inhibitor development in Chinese patients with haemophilia A

Summary

One of the most severe and important complication in the treatment of haemophilia A (HA) patients is the formation of inhibitors. The mechanism that leads to factor (F)VIII inhibitor formation is complicated. Both genetic and environmental factors have been mentioned to play decisive roles. Recently, polymorphisms in the genes encoding interleukin-10 (IL-10), tumour necrosis factor-alpha (TNF-α), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been suggested to be contributing determinants of the inhibitor risk. In order to investigate the influence of the single nucleotide polymorphisms (SNPs) in the genes encoding for cytokines to the inhibitors development in Chinese HA patients, we genotyped 10 SNPs with high heterozygote rates in Chinese and a CA repeat microsatellite at the gene loci IL-10 as well in a separate, unrelated case-controlled cohort of 122 affected HA patients; 63 with inhibitors and 59 without inhibitors. The particular SNPs included in this study were as follows: –592C/A and –819C/T in IL-10, –590C/T in IL-4, –318C/T and 49A/G in CTLA-4, –827C/T in TNF-α, –1112C/T and 2044G/A in IL-13, 874A/T in interferon (IFN)-γ and –295T/C in IL-16. Our results demonstrated that –819T and –592A alleles in IL-10 were observed more frequently in patients with inhibitors. This indicated that –819C/T and –592A/C in IL-10 may influence the inhibitors development in HA patients. Furthermore, we concluded that the haplotype in IL-10 (TA, CA, CC at positions –819 and –582, respectively) may predispose FVIII inhibitor development in HA patients. In conclusion, the data reported in our study clearly highlight the participation of IL-10 in inhibitors formation in Chinese HA patients.

Keywords

Haemophilia A - inhibitors - polymorphisms - cytokine

• References

• 1 Pavlova A, Delev D, Lacroix-Desmazes S. et al. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-a and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost 2009; 07: 2006-2015.
• 2 Oldenburg J, Schroder J, Brackmann HH. et al. Environmental and genetic factors influencing inhibitor development. Semin Hematol 2004; 41 (01) 82-88.
• 3 Gouw SC, van den Berg HM, Le Cessie S, van der Bom JG. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia. J Thromb Haemost 2007; 05: 1383-1390.
• 4 Astermark J, Oldenburg J, Carlson J. et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 2006; 108: 3739-3745.
• 5 Astermark J, Oldenburg J, Escobar M. et al. Malmo International Brother Study study group. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica 2005; 90: 924-931.
• 6 Lacroix-Desmazes S, Navarrete AM, Andre S. et al. Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A. Blood 2008; 15: 240-249.
• 7 Astermark J, Oldenburg J, Pavlova A. et al. Polymorphisms in the IL10 but not in the ILlbeta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 2006; 107: 3167-3172.
• 8 Astermark J, Wang X, Oldenburg J. et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007; 05: 263-265.
• 9 Hiromatsu Y, Fukutani T, Ichimura M. et al. Interleukin-13 Gene Polymorphisms Confer the Susceptibility of Japanese Populations to Graves’ Disease. J Clin Endocrinol Metab 2005; 90: 296-301.
• 10 Rekha PL, Ishaq M, Valluri V. A Differential Association of Interferon-r High-Producing Allele T and Low-Producing Allele A (+874 A/T) with Hashimoto’s Thyroiditis and Graves’ Disease. Scand J Immunol 2006; 64: 438-443.
• 11 Nakayama EE, Wasi C, Ajisawa A. et al. A new polymorphism in the promoter region of the human interleukin-16 (IL-16) gene. Genes Immun 2000; 01: 293-294.
• 12 Yee LJ, Tang J, Gibson AW. et al. Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology 2001; 33: 708-712.
• 13 Rees LE, Wood NA, Gillespie KM. et al. The interleukin-10–1082G/A polymorphism: allele frequency in different populations and functional significance. Cell Mol Life Sci 2002; 59: 560-569.
• 14 Lacroix-Desmazes S, Navarrete AM, Andre S. et al. Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A. Blood 2008; 15: 240-249.
• 15 Eskdale J, Gallagher G, Verweij CL. et al. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998; 95: 9465-9470.
• 16 Eskdale J, Keijsers V, Huizinga T. et al. Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1999; 01: 151-155.
• 17 Djukanovic R. The role of co-stimulation in airway inflammation. Clin Exp Allergy 2000; 30: S46-50.
• 18 Hausl C, Ahmad RU, Schwarz HP. et al, Reipert BM Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibodydependent immune disorders. Blood 2004; 104: 115-122.
• 19 Pavlova A, DiazLacava A, Zeitler H. et al. Increased frequency of the CTLA4 + 49 A/ G polymorphism in patients with acquired haemophilia A compared to healthy controls. Haemophilia 2008; 14: 355-360.