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

• Published in: Journal of thrombosis and haemostasis Vol. 21; no. 4; pp. 800 - 813
• Main Authors: Ahmed, Anwar E., Pratt, Kathleen P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2023
• Subjects: Ethnicity; F8 haplotypes; Factor VIII - genetics; hemophilia A; Hemophilia A - diagnosis; Hemophilia A - genetics; Humans; inhibitors; intron-22 inversion; Introns; Mutation; ns-SNPs; hemophilia A; inhibitors; F8 haplotypes; ns-SNPs; intron-22 inversion
• ISSN: 1538-7836; 1538-7836
• DOI: 10.1016/j.jtha.2022.12.017

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. 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. 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. Black and Hispanic severe HA subjects had a higher inhibitor risk than non-Hispanic 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. 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. •The My Life Our Future repository contains data on >6000 hemophilia A subjects.•Regression analyses of clinical and F8 gene sequence data were carried out.•Intron-22 inversions carry similar inhibitor risk as other large disruptions of the F8 gene.•Increased inhibitor risk of Black subjects was not associated with ns-SNPs in the F8 gene.