Genetic factors influencing inhibitor development in a cohort of South African haemophilia A patients

Abstract

A critical complication of factor VIII (FVIII) replacement therapy in Haemophilia A (HA) treatment is inhibitor development. Known genetic factors predisposing to inhibitor development include FVIII (F8) gene mutations, ethnicity, a family history of inhibitors and FVIII haplotype mismatch. The aim of this study was to characterize and correlate these genetic factors in a cohort of South African HA patients. This was a retrospective study that included 229 patients and involved the analysis of patient files, HA molecular and clinical databases and molecular analysis of the F8 gene haplotype. Of the 229 patients, 51% were of black ethnicity, 49% were white, 5% had mild HA, 4% were moderate and 91% were severe, 36% were int22 positive and 13% were inhibitor positive. Of the inhibitor positive patients, 72% were black patients. Inhibitors were reported in 27% of black int22 positive patients, 13% of black int22 negative patients, 9% of white int22 positive patients and 7% of white int22 negative. The H1 haplotype was more common in whites (75%) and H2 was more common in blacks (74%). H3 and H5 were only found in black patients and had a higher frequency of inhibitor development than H1 and H2. In this small HA cohort, black patients had a significantly higher frequency of inhibitor development and the results were indicative of an association between inhibitor development, ethnicity and haplotype.

Factor VIII gene variants and inhibitor risk in African American hemophilia A patients

“…14 Subsequent studies have not shown a statistical link between F8 polymorphisms and inhibitor incidence. [27][28][29] The present study focuses primarily on inhibitor incidence in patients with severe HA. Seven subjects who had an intron-22 inversion mutation but baseline clotting activity $1% normal were also included, as they are not expected to circulate FVIII.…”

“…28 Multiple-exon deletions have been shown to carry the largest inhibitor risk for patients with severe HA, whereas missense mutations and small insertions/deletions carry lower risks. 2 The race-associated inhibitor risks associated with these types of mutations could not be determined because the subgroups in this study were too small.…”

Recent Advances in Application of Pharmacogenomics for Biotherapeutics

“…Recently, this approach has been applied to understand genetic basis of immunogenicity to recombinant Factor VIII, a BT used for treatment of hemophilia A (66)(67)(68)(69)(70). A growing body of literature points to influence of human genetic variability on efficacy as well as tolerability/ adverse effects of a number of vaccines (reviewed in ref.…”

Game, set, match for factor VIII mismatch?

“…4 Subsequent studies of small populations of patients of African ancestry have failed to confirm this finding. 5–7 The haplotypes investigated are rare in White populations, and no correlation with inhibitors was found in substantially sized groups of White patients. 5, 8 …”