F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

Summary Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes an...

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Published in:	Haemophilia : the official journal of the World Federation of Hemophilia Vol. 19; no. 1; pp. 113 - 118
Main Authors:	Schwarz, J., Astermark, J., Menius, E. D., Carrington, M., Donfield, S. M., Gomperts, E. D., Nelson, G. W., Oldenburg, J., Pavlova, A., Shapiro, A. D., Winkler, C. A., Berntorp, E.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-01-2013
Subjects:	Antibodies Autoantibodies - blood Blood Coagulation Factor Inhibitors - blood Clinical Medicine Coagulation factors Cohort Studies Data processing DNA Mutational Analysis F8 haplotype Factor VIII - antagonists & inhibitors Factor VIII - genetics FVIII inhibitors Genetic Predisposition to Disease haplotype mismatch Haplotypes Haplotypes - genetics Hematologi Hematology Hemophilia Hemophilia A - genetics Hemophilia A - immunology Histocompatibility antigen HLA Humans Klinisk medicin Leukocytes Medical and Health Sciences Medicin och hälsovetenskap Mutation Risk factors
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Summary:	Summary Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
Bibliography:	ArticleID:HAE12004 ark:/67375/WNG-0Z898P8B-B istex:A6885DB1571AC8BBF856AA6E6F1F06115F1C3DBE ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1351-8216 1365-2516 1365-2516
DOI:	10.1111/hae.12004