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

Blood ◽  
2015 ◽  
Vol 125 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Zuben E. Sauna ◽  
Jay N. Lozier ◽  
Carol K. Kasper ◽  
Chen Yanover ◽  
Timothy Nichols ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Amino Acid ◽  
Amino Acid Sequence ◽  
Factor Viii ◽  
Class Ii ◽  
Hla Class Ii ◽  
Intron 22 Inversion ◽  
Histocompatibility Complex ◽  
Foreign Peptide ◽  
The Stability

Abstract 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 any HLA class-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.

Relationship of Major Histocompatibility Complex Class II Genes to Inhibitor Antibody Formation in Hemophilia A

1990 ◽  
Vol 64 (04) ◽  
pp. 564-568 ◽  
Author(s):  
Lloyd E Lippert ◽  
Lyman Mc A Fisher ◽  
Lawrence B Schook
Keyword(s):  
Major Histocompatibility Complex ◽  
Factor Viii ◽  
Antibody Formation ◽  
Rflp Analysis ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Odds Ratios ◽  
Inhibitory Antibody ◽  
Histocompatibility Complex ◽  
Hla Dr

SummaryApproximately 14% of transfused hemophiliacs develop an anti-factor VIII inhibitory antibody which specifically neutralizes factor VIII procoagulant activity. In this study an association of the major histocompatibility complex (MHC) with inhibitor antibody formation was evaluated by restriction fragment length polymorphism (RFLP) analysis using BamHI, EcoRI, HindII, PstI, PvuII and TaqI digested genomic DNA probed with DP beta, DQ alpha, DQ beta and DR beta class II MHC gene probes. The RFLP patterns for 16 non-inhibitor and 11 inhibitor hemophiliac patients were analyzed. These 24 enzyme:probe combinations generated 231 fragments. Fifteen (15) fragments associated with the inhibitor phenotype; odds ratios ranged from 5.1 to 45 and lower bounds of 95% confidence intervals were > 1.000 for all 15 fragments. Five (5) fragments associated with non-inhibitors, with odds ratios ranging from 6.4 to 51.7. This report establishes a MHC related genetic basis for the inhibitor phenotype. No statistically significant differences in the distribution of serologically defined HLA-DR phenotypes were observed between the inhibitor and non-inhibitor groups.

Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis

1996 ◽  
Vol 134 (4) ◽  
pp. 449-453 ◽  
Author(s):  
Arthur B Parkes ◽  
Christopher Darke ◽  
Sakinah Othman ◽  
Melanie Thomas ◽  
Neil Young ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class Ii ◽  
Hla Class Ii ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class Iii ◽  
Postpartum Thyroiditis ◽  
Histocompatibility Complex ◽  
Hla Dr

Parkes AB, Darke C, Othman S, Thomas M, Young N, Richards CJ, Hall R, Lazarus JH. Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis. Eur J Endocrinol 1996;134:449–53. ISSN 0804–4643 The objective was to re-evaluate the association between class II HLA-DR and DQ MHC antigens and postpartum thyroiditis (PPT) and to determine the prevalence of the class III complement allotypes of Properdin factor B (Bf), C4A and C4B in this condition. Two hundred and sixty-five (of 2897) pregnant women screened positive for thyroid autoantibody activity took part. Further blood samples were obtained for HLA class II (185) and complement (193) typing. The severity of the ensuing PPT was assessed by measuring thyroid function during the postpartum year. The HLA-DR and DQ phenotypes were assigned from restriction fragment length polymorphism analysis, and Bf, C4A and C4B allotypes were determined by immunofixation with anti-Bf or anti-C4 antibodies after electrophoresis. A weak association between the HLA class II antigens and PPT, as indicated by a reduced frequency of DR15 and DQ6 together with an increased frequency of DR5 and DQ7. was confirmed. However, only the change in DR5 frequency remained significant after correction (corrected p < 0.05). Postpartum thyroiditis was also associated with frequency disturbances in Bf and C4A allotypes but not C4B allotypes. Whilst this study has not provided evidence of a strong marker gene for PPT, it does not preclude the involvement of the MHC in this condition. These data show disturbances in complement allotype frequencies, suggesting that the class III region may provide a useful focus for further study of this pathology. AB Parkes, Autoimmunology Research Unit, Section of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK

Characterization of three separated exons in the HLA class II DR region of the human major histocompatibility complex

1995 ◽  
Vol 42 (3) ◽  
pp. 254-264 ◽  
Author(s):  
Ann-Kristin Arvidsson ◽  
Ann-Cathrin Svensson ◽  
Eva Widmark ◽  
Göran Andersson ◽  
Lars Rask ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Class Ii ◽  
Hla Class Ii ◽  
Major Histocompatibility ◽  
Human Major Histocompatibility Complex ◽  
Histocompatibility Complex
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