Race, ethnicity, F8 variants, and inhibitor risk: analysis of the "My Life Our Future" hemophilia A database

Background: Several studies have suggested Black and Hispanic hemophilia A (HA) patients in the United States suffer higher incidences of neutralizing anti-FVIII antibodies (inhibitors) than their White counterparts. The possible influence of nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene sequence has been proposed as a possible race-associated contributing factor. Some earlier studies indicated that intron-22 inversion mutations carry a lower inhibitor risk than other mutations resulting in large F8 gene disruptions. Objectives: The objectives of the study were to test the following hypotheses: (1) The risk of developing an inhibitor differs among racial/ethnic groups in the United States, (2) specific non-HA-causing ns-SNPs in the F8 gene are correlated with inhibitor risk, and (3) inhibitor risk associated with intron-22 inversions mutations is similar to that associated with other large structural changes in the F8 gene. Methods: Adjusted logistic regression analysis of the "My Life Our Future" database containing demographic, clinical, and F8 sequence data from > 6000 mild, moderate, and severe HA participants. Results: Black and Hispanic severe HA subjects had a higher inhibitor risk than nonHispanic Whites (adjusted odds ratio = 1.65, 95% CI: 1.22-2.21 and adjusted odds ratio = 1.88, 95% CI: 1.43-2.48), confirming this racial/ethnic/medical disparity; however, F8 ns-SNPs were not associated with inhibitor development. There was no difference in inhibitor risk among severe HA subjects with an intron-22 inversion vs other large structural changes in the F8 gene. Conclusions: Nonpathogenic ns-SNPs in the F8 gene are not correlated with inhibitor risk. Inhibitor risk associated with intron-22 inversion mutations is similar to that of other large structural changes in F8 that preclude intact FVIII expression.