HLA Genotype of Patients with Severe Haemophilia A due to Intron 22 Inversion with and without Inhibitors of Factor VIII

Summary

Molecular genetic studies have shown that development of antibodies to factor VIII (inhibitors) occurs most frequently in patients with severe haemophilia due to major gene lesions including inversions, stop codons and large deletions. Previous studies of HLA type were performed on inhibitor and non-inhibitor patients with diverse uncharacterised mutations which may have confounded detection of significant associations. We therefore selected a group of patients with a single mutation type, the prevalent intron 22 inversion, with or without inhibitors, to determine HLA genotype. Seventy-one such patients, 42 without and 29 with inhibitors (13 high, 9 low and 7 transient responders) were genotyped for MHC Class I HLA-A, -B, -C and Class II HLA-DQA, -DQB and -DRB loci. No strong correlation of any HLA-allele to inhibitor or non-inhibitor status was found. However, alleles of the haplotype HLA-A3, HLA-B7, HLA-C7, HLA-DQA0102, HLA-DQB0602, HLA-DR15 occurred more often in inhibitor patients. Since the alleles of this extended haplotype are common in the North European population only a very strong association would achieve statistical significance. Further studies of groups of patients similar to those studied here will be needed to confirm or exclude this association.

• References

• 1 Scharrer I, Neutzling O. Incidence of inhibitors in haemophiliacs. A review of the literature. Blood Coag Fibrinol 1993; 04: 753-758
• 2 Brackmann HH, Gormsen J. Massive Factor VIII Infusion in a Haemophiliac with Factor VII Inhibitor High Response. Lancet 1977; 02: 933
• 3 Mariani G, Scheibel E, Nagao T, Kasper CK, Ewing NP, Mauser-Bunscho-ten E, Ghirardini A, Bellocco R, Brackmann HH. Immunetolerance as Treatment of Alloantibodies to Factor VIII in Hemophilia. The International Registry of Immunetolerance Protocols. Semin Hematol 1994; 31 (02) (Suppl. 04) 62-64
• 4 Schwaab R, Brackmann H-H, Meyer C, Seehafer J, Kirchgesser M, Haack A, Olek K, Tuddenham EGD, Oldenburg J, Haemophilia A. Mutation type determines risk of inhibitor formation Haemost Thrombosis 1995; 74: 1402-1406
• 5 Frommel D, Muller JY, Prou-Wartelle O, Allain JP. Possible Linkage between the Major Histocompatibility Complex and the Immune Response to Factor VIII in Classical Haemophilia Vox Sang 1977; 33: 270-272
• 6 Frommel D, Allain JP, Saint-Paul E, Bosser C, Noel B, Mannucci PM, Pannicucci F, Blombäck M, Prou-Wartelle O, Muller JY. HLA Antigens and Factor VIII Antibody in Classic Hemophilia. Thromb Haemost 1981; 46: 687-689
• 7 Lippert LE, Fisher JMcA, Schook LB. Relationship of Major Histocompatibility Complex Class II Genes to Inhibitor Formation in Haemophilia A Thromb Haemost 1990; 64: 564-568
• 8 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungot T, Krackhardt B, Kornhuber B. Incidence of Development of Factor VIII and Factor IX Inhibitors in Haemophiliacs. Lancet 1992; 339: 594-598
• 9 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, Lazerson J. Hemophilia Study Group: The Natural History of Factor VIII:C Inhibitors in patients with Hemophilia A: A national Cooperative Study. II. Observations on the Initial Development of Factor VIII: C. Blood 1988; 71: 344-348
• 10 Aledort L. Inhibitors in Hemophilia Patients: Current Status and Management. Am J Hematol 1994; 47: 208-217
• 11 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgardner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, von EysJ. A more Uniform Measurement of Factor VIII Inhibitors. Thrombos diathes Haemorrh 1975; 34: 869-872
• 12 Lakich D, Kazazian HH, Antonorakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genetics 1993; 05: 236-241
• 13 Picard JK. Single-step allele-specific polymerase chain reaction HLA-DQ genotyping using ARMS primers Hum Immunol 1993; 38: 115-122
• 14 Altmann DM, Sansom S, Marsh SGE. What is the basis for HLA-DQ associations with autoimmune disease?. Immunol Today 1991; 12: 267
• 15 Fisher RA. The Design of Experiments. Edinburgh: Oliver & Boyd. 1960
• 16 Dunn OJ. Estimation of the Means of Dependent Variables. Ann Math Stat 1958; 29: 1095-111
• 17 Dunn OJ. Multiple Comparisons among Means. Am J Stat Assoc 1961; 56: 52-64
• 18 Woolfe B. On Estimating the Relation between Blood Group and Disease. Ann Hum Genet 1955; 19: 251-253
• 19 Haldane JBS. The Estimation and Significance of the Logarithm of a Ratio of Frequencies. Ann Hum Genet 1956; 20: 309-311
• 20 Chicz RM, Urban RG, Gorga JC, Vignali DAA, Lane WS, Strominger JL. Specifity and Promiscuity among Naturally Processed Peptides Bound to HLA-DR Alleles. J Exp Med 1993; 178: 27-47
• 21 European Study Group of Factor VIII Antibody. Development of Factor VIII Antibody in Haemophilic Monozygotic Twins. Scand J Haematol. 1979 23. 64-68
• 22 Aly AM, Aledort LM, Lee TD, Hoyer LW. Histocompatibility Antigen Pattern in Haemophilic Patients with Factor VIII Antibodies. Brit J Haematol 1990; 76: 238-241
• 23 Simmoney N, De Bosch N, Argueyo A, Garcia E, Layrise Z. HLA Antigens in Hemophiliacs A with or without Factor VIII Antibodies in a Venezuelan Mestizo Population. Tissue Antigens 1985; 25: 216-219
• 24 Mayr WR, Lechner K, Niessner H, Pabinger-Fasching I. HLA-DR and Factor VIII Antibodies in Haemophilia A. Thromb Haemost 1984; 51: 293 (letter).