Inhibitor Risk Paper Informed by Genotyping Project
Between 2013-2017, the “My Life Our Future” (MLOF) project offered eligible individuals with hemophilia free genotyping, which is historically hard to access, expensive, and not covered by insurance. Conducted through the laboratory analysis of a single blood sample, genotyping can reveal the specific genetic mutation responsible for a patient’s disease such as those located in the factor VIII and factor IX genes in the case of hemophilia A (HA) and hemophilia B respectively.
MLOF was a partnership between the hemophilia community, the National Hemophilia Foundation, American Thrombosis and Hemostasis Network (ATHN), Bloodworks Northwest, and Bioverativ/Sanofi (formerly Biogen). Individuals who participated in the program could also opt – via informed consent – to have a blood sample with their de-identified genome sequence data deposited into the MLOF Research Repository. Investigators could apply for access to the database to support their research, with acceptance contingent upon their ability to demonstrate both scientific merit and ultimate benefit to patients.
Ultimately, samples from more than 6,000 individuals were included in the repository to help advance the scientific understanding of the disorder. MLOF was a boon to researchers, particularly to those looking to better understand the genetic differences that affect bleeding severity and reactions to certain therapies. One such example is a new paper “Race, Ethnicity, F8 Variants, and Inhibitor Risk: Analysis of the ‘My Life Our Future’ Hemophilia A Database,” published in the Journal of Thrombosis and Haemostasis.
Armed with ample collection of samples generated by MLOF, the authors of the paper sought to investigate some existing hypotheses related to inhibitor risk amongst individuals with HA.
A total of 4169 subjects were included in the primary analysis, 2,443 with severe HA and 1726 with mild or moderate HA – this analysis examined several key variables including demographic, clinical, factor VIII gene (F8) sequence data. Investigators found inhibitor incidences of 30.3% in those with severe HA and 7.9% in the mild/moderate group. In the severe group, 1075 (44%) had an intron-22 inversion mutation of the F8 gene, and of those, 388 (36.1%) developed an inhibitor.
The result of a crossing over between two linked gene pairs of the same chromosome, intron 22 inversions account for nearly 50% of severe hemophilia A cases. Investigators sought to determine whether inhibitor risk associated with these type mutations are similar to those associated with other large structural changes in the F8 gene. They ultimately found no difference in inhibitor risk amongst those severe HA participants with an intron-22 inversion vs other large structural changes in the F8 gene.
The authors also looked at another hypothesis informed by earlier research which suggested that increased inhibitor risk could be caused by specific mutations known as non-HA causing, non-synonymous single nucleotide polymorphisms (nsSNPs). Often associated with disease, nsSNPs are caused by a change to the amino acid sequence of a genetically encoded protein. In fact, the analysis showed that nonpathogeic ns-SNPs in the F8 were not associated with inhibitor development.
The analysis also confirmed earlier studies suggesting an increased risk for FVIII inhibitor development in both Black/African American and Hispanic HA patients, relative to White non-Hispanic individuals with HA in the U.S.
Investigators signaled the potential implications of this study, and future research, in helping to inform therapeutic plans that better anticipate inhibitor risk.
“It is hoped that future studies, e.g., whole-genome sequence analyses to detect genetic variations contributing to inhibitor risk, will identify specific, clinically actionable genetic correlates indicating increased susceptibility to, or protection from, hemophilic inhibitor development and possibly suggesting novel therapeutic interventions to promote immune tolerance to FVIII,” concluded the authors.
Citation
Ahmed AE, Pratt KP. Race, ethnicity, F8 variants, and inhibitor risk: analysis of the "My Life Our Future" hemophilia A database. J Thromb Haemost. 2023 Apr;21(4):800-813. doi: 10.1016/j.jtha.2022.12.017. Epub 2022 Dec 26. Erratum in: J Thromb Haemost. 2023 Apr 25;: PMID: 36696179.
Visit the Journal of Thrombosis and Haemostasis to view the abstract.
NOTE: Corrigendum to ‘Race, ethnicity, F8 variants and inhibitor risk: Analysis of the “My Life Our Future” Hemophilia A database’ [Journal of Thrombosis and Haemostasis Volume 21, Issue 4, April 2023, Pages 800-813]
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