title: Factor VIII gene variants and inhibitor risk in African American hemophilia A patients.
abstract: African American hemophilia A (HA) patients experience a higher incidence of neutralizing anti-factor VIII (FVIII) antibodies ("inhibitors") vis-à-vis white patients. Nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-H484, FVIII-E1241, and FVIII-V2238 are more prevalent in African Americans. This study tested the hypothesis that immune responses to these sites provoke inhibitors. Blood samples were obtained from 174 African American and 198 white HA subjects and their F8 gene sequences determined. Major histocompatibility complex class II binding and T-cell recognition of polymorphic sequences were evaluated using quantitative binding assays and HLA-DRB1 tetramers. Peptides corresponding to 4 common ns-SNPs showed limited binding to 11 HLA-DRB1 proteins. CD4 T cells from 22 subjects treated with FVIII products having sequences at residues FVIII-484, 1241, and 2238 differing from those of putative proteins encoded by their F8 genes did not show high-avidity tetramer binding, whereas positive-control staining of tetanus-specific CD4 T cells was routinely successful. African Americans with an intron-22 inversion mutation showed a 2-3 times-higher inhibitor incidence than whites with the same mutation (odds ratio = 2.3 [1.1-5.0, P = .04]), but this did not correlate with any of the ns-SNPs. We conclude that immune responses to "sequence-mismatched" FVIII products are unlikely to contribute appreciably to the inhibitor incidence in African Americans.
authors.affiliation: Uniformed Services University of the Health Sciences, Bethesda, MD; Puget Sound Blood Center Research Institute, Seattle, WA;
authors.forename: Devi
authors.initials: D
authors.lastname: Gunasekera
authors.affiliation: Puget Sound Blood Center Research Institute, Seattle, WA;
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ettinger
authors.affiliation: Genomics Laboratory, Puget Sound Blood Center, Seattle, WA;
authors.forename: Shelley
authors.initials: S
authors.lastname: Nakaya Fletcher
authors.affiliation: Benaroya Research Institute, Seattle, WA;
authors.forename: Eddie A
authors.initials: EA
authors.lastname: James
authors.affiliation: Puget Sound Blood Center Research Institute, Seattle, WA;
authors.forename: Maochang
authors.initials: M
authors.lastname: Liu
authors.affiliation: Central Virginia Center for Coagulation Disorders, Virginia Commonwealth University, Richmond, VA;
authors.forename: John C
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Palmetto Health, Columbia, SC;
authors.forename: Janice
authors.initials: J
authors.lastname: Withycombe
authors.affiliation: Pediatrics/Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA; and.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Matthews
authors.affiliation: Department of Pathology and Laboratory Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Epstein
authors.affiliation: Department of Pathology and Laboratory Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hughes
authors.affiliation: Uniformed Services University of the Health Sciences, Bethesda, MD; Puget Sound Blood Center Research Institute, Seattle, WA;
authors.forename: Kathleen P
authors.identifier: http://orcid.org/0000-0001-6837-6133
authors.initials: KP
authors.lastname: Pratt
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000097:blood*; D001323:Autoantibodies / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018604:Epitope Mapping; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D014644:Genetic Variation; D059811:HLA-DRB1 Chains / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D006467:Hemophilia A / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012307:Risk Factors; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D059811:HLA-DRB1 Chains; D050505:Mutant Proteins; D010446:Peptide Fragments; C078147:F8 protein, human; D005169:Factor VIII