F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort
Open Access
- 7 September 2012
- journal article
- research article
- Published by Wiley in Haemophilia
- Vol. 19 (1), 113-118
- https://doi.org/10.1111/hae.12004
Abstract
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.Keywords
This publication has 23 references indexed in Scilit:
- 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 AJournal of Thrombosis and Haemostasis, 2009
- Inhibitors of Factor VIII in Black Patients with HemophiliaNew England Journal of Medicine, 2009
- Polymorphisms in the CTLA‐4 gene and inhibitor development in patients with severe hemophilia AJournal of Thrombosis and Haemostasis, 2007
- Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia ABlood, 2006
- Principal components analysis corrects for stratification in genome-wide association studiesNature Genetics, 2006
- Review: A gentle introduction to imputation of missing valuesJournal of Clinical Epidemiology, 2006
- Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin‐free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A1Haemophilia, 2004
- The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor developmentHaemophilia, 2001
- Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma‐derived factor VIII concentratesHaemophilia, 1999
- Inversions disrupting the factor VIII gene are a common cause of severe haemophilia ANature Genetics, 1993