F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity

Abstract

Both genetic and treatment-related risk factors contribute to the development of inhibitors in haemophilia. An inhibitor surveillance system piloted at 12 US sites has the goal of assessing risk factors through prospective data collection. This report examines the relationship of genotype and race/ethnicity to history of inhibitor in a large cohort of US haemophilia patients. Mutation analysis was performed on 676 haemophilia A (HA) and 153 haemophilia B (HB) patients by sequencing, Multiplex Ligation-dependent Probe Amplification, and PCR for inversions in F8 introns 22 (inv22) and 1 (inv1). Two HB patients with deletions had history of inhibitor. In severe HA, frequency of history of inhibitor was: large deletion 57.1%, splice site 35.7%, inv22 26.8%, nonsense 24.5%, frameshift 12.9%, inv1 11.1% and missense 9.5%. In HA, 19.6% of 321 White non-Hispanics (Whites), 37.1% of 35 Black non-Hispanics (Blacks) and 46.9% of 32 Hispanics had history of inhibitor (P = 0.0003). Mutation types and novel mutation rates were similar across ethnicities. When F8 haplotypes were constructed, Whites and Hispanics showed only H1 and H2. Within H1, history of inhibitor was 12.4% in Whites, 40.0% in Blacks (P = 0.009) and 32.4% in Hispanics (P = 0.002). Inhibitor frequency is confirmed to vary by mutation type and race in a large US population. White patients with history of inhibitor did not exhibit rare F8 haplotypes. F8 gene analysis did not reveal a cause for the higher inhibitor frequencies in Black and Hispanic patients.

Haemophilia B acquired from liver transplantation: a case report and literature review

“…This F9 mutation has been identified previously in other patients with mild haemophilia B [4] and appears to be more common in the African American population. Of note, the liver donor was a 14-yearold African American male who died of a subdural haematoma after a fall.…”

Personalized Approaches to the Treatment of Hemophilia A and B

“…The hypothesis that mismatches in the sequences due to some polymorphisms could be the cause of a higher incidence of nADAs among African-American patients [16,28,30] has however, not been experimentally verified and the underlying mechanism for this clinical observation are not understood. The study is also controversial as a similar correlation between sequence mismatch due to polymorphisms and increased prevalence of nADAs has not been observed in two additional studies [31,32].…”

T cell response to FVIII

“…In contrast to these observations, other recent studies have not found any statistical association between F8 polymorphisms and inhibitor incidence [32][33][34]. One such study sought to determine whether African American patients with hemophilia A and inhibitor have FVIII-specific T cells that are able to distinguish between normal FVIII concentrates and FVIII peptides carrying alternative ns-SNPs [34].…”