The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics

被引：23

作者：

Sauna, Zuben E. ^{[1
]}

Lozier, Jay N. ^{[2
]}

Kasper, Carol K. ^{[3
,4
]}

Yanover, Chen ^{[5
]}

Nichols, Timothy ^{[6
,7
]}

Howard, Tom E. ^{[8
,9
,10
]}

机构：

[1] US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA

[2] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA

[3] Orthopaed Hemophilia Treatment Ctr, Los Angeles, CA USA

[4] Univ So Calif, Keck Sch Med, Dept Med, Div Hematol, Los Angeles, CA 90033 USA

[5] IBM Res Lab, Machine Learning Healthcare & Life Sci, Haifa, Israel

[6] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA

[7] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA

[8] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Los Angeles, CA 90073 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[10] Univ So Calif, Keck Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90033 USA

来源：

BLOOD | 2015年 / 125卷 / 02期

基金：

美国国家卫生研究院;

关键词：

SEVERE HEMOPHILIA-A; ENDOGENOUS FACTOR-VIII; MHC CLASS-II; CENTRAL TOLERANCE; GENE; MUTATION; MILD; CELLS; IMMUNOGENICITY; INVERSIONS;

D O I：

10.1182/blood-2013-12-530113

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM" status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for anyHLAclass-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire.

引用

页码：223 / 228

页数：6

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