Ethnicity-specific impact of HLA I/II genotypes on the risk of inhibitor development: data from Korean patients with severe hemophilia A
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Inhibitor development is the most serious complication in patients with hemophilia. We investigated association of HLA genotypes with inhibitor development in Korean patients with severe hemophilia A (HA). HLA genotyping was done in 100 patients with severe HA including 27 patients with inhibitors. The allele frequencies between inhibitor-positive and inhibitor-negative patients were compared. HLA class I alleles were not associated with the inhibitor status. In HLA class II, DRB1*15 [n = 100, odds ratio (OR) 0.217, P = 0.028] and DPB1*05:01 [OR 0.461, P = 0.026] were negatively associated with inhibitor development. In a subgroup of patients with intron 22 inversion, C*07:02 was positively associated with inhibitor development [n = 30, OR 5.500, P = 0.043]. In the subgroup of patients without intron 22 inversion, the negative association between DPB1*05:01 and inhibitor development was reinforced [n = 70, OR 0.327, P = 0.010], and positive association of DRB1*13:02 and DPB1*04:01 with inhibitor development was identified [OR 3.059, P = 0.037 for both]. Previously reported risk alleles were not consistently associated with inhibitor risk in our series. This study demonstrated the profile of HLA alleles associated with inhibitor risk in Korean patients with severe HA was different from that in patients of other ethnicities, which needs to be considered in risk assessment and management.
KeywordsHemophilia A Inhibitor HLA genotypes Mutation Korea
This study was supported by a grant from the Korea Food & Drug Administration (KFDA) and by a grant from Korea Hemophilia Foundation.
Compliance with ethical standards
This study was approved by the Institutional Review Board of Samsung Medical Center (Seoul, Korea), and all patients gave written informed consent in accordance with the Declaration of Helsinki.
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Chalmers EA, Brown SA, Keeling D, Liesner R, Richards M, Stirling D, Thomas A, Vidler V, Williams MD, Young D (2007) Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 13:149–155. https://doi.org/10.1111/j.1365-2516.2006.01418.x CrossRefPubMedGoogle Scholar
- 5.Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, Thompson AR, van Heerde W, Boekhorst J, Miller CH, le Cessie S, van der Bom JG (2012) F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 119:2922–2934. https://doi.org/10.1182/blood-2011-09-379453 CrossRefPubMedGoogle Scholar
- 6.Pandey GS, Yanover C, Miller-Jenkins LM, Garfield S, Cole SA, Curran JE, Moses EK, Rydz N, Simhadri V, Kimchi-Sarfaty C, Lillicrap D, Viel KR, Przytycka TM, Pierce GF, Howard TE, Sauna ZE, Investigators PS (2013) Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A. Nat Med 19:1318–1324. https://doi.org/10.1038/nm.3270 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Pavlova A, Delev D, Lacroix-Desmazes S, Schwaab R, Mende M, Fimmers R, Astermark J, Oldenburg J (2009) 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. J Thromb Haemost 7:2006–2015. https://doi.org/10.1111/j.1538-7836.2009.03636.x CrossRefPubMedGoogle Scholar
- 18.Wieland I, Wermes C, Eifrig B, Holstein K, Pollmann H, Siegmund B, Bidlingmaier C, Kurnik K, Nimtz-Talaska A, Niekrens C, Eisert R, Tiede A, Ebenebe C, Lakomek M, Hoy L, Welte K, Sykora KW (2008) Inhibitor-Immunology-Study. Different HLA-types seem to be involved in the inhibitor development in haemophilia A. Hamostaseologie 28(Suppl 1):S26–S28PubMedGoogle Scholar
- 19.De Barros MF, Herrero JC, Sell AM, De Melo FC, Braga MA, Pelissari CB, Machado J, De Souza Schiller S, De Souza Hirle L, Visentainer JE (2012) Influence of class I and II HLA alleles on inhibitor development in severe haemophilia A patients from the south of Brazil. Haemophilia 18:e236–e240. https://doi.org/10.1111/j.1365-2516.2011.02604.x CrossRefPubMedGoogle Scholar
- 20.Pergantou H, Varela I, Moraloglou O, Economou M, Spanou K, Kapsimali Z, Constantinidou N, Platokouki H (2013) Impact of HLA alleles and cytokine polymorphisms on inhibitors development in children with severe haemophilia A. Haemophilia 19:706–710. https://doi.org/10.1111/hae.12168 CrossRefPubMedGoogle Scholar
- 22.Lamberth K, Reedtz-Runge SL, Simon J, Klementyeva K, Pandey GS, Padkjaer SB, Pascal V, Leon IR, Gudme CN, Buus S, Sauna ZE (2017) Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools. Sci Transl Med 9:eaag1286. https://doi.org/10.1126/scitranslmed.aag1286 CrossRefPubMedGoogle Scholar
- 23.Pashov AD, Calvez T, Gilardin L, Maillere B, Repesse Y, Oldenburg J, Pavlova A, Kaveri SV, Lacroix-Desmazes S (2014) In silico calculated affinity of FVIII-derived peptides for HLA class II alleles predicts inhibitor development in haemophilia A patients with missense mutations in the F8 gene. Haemophilia 20:176–184. https://doi.org/10.1111/hae.12276 CrossRefPubMedGoogle Scholar