HLA Class II Profile: A Weak Determinant of Factor VIII Inhibitor Development in Severe Haemophilia A

Summary

The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (>10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion.

HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies from 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA- DRB*1501, DQB 1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7,1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB 1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB 1*01, DQB 1 *0501, DQA 1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.

• References

• 1 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. and the Kogenate study group Recombinant factor VIII for the treatment of previously untreated patients with haemophilia A. N Eng J Med 1993; 328: 453-459
• 2 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598
• 3 Addiego J, Kasper C, Abildgaard C, Hildgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in haemophiliacs treated with intermediate-purity VIII. Lancet 1993; 342-364
• 4 Rizza CR, Spooner RGD. Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976-1980: report on behalf of the directors of the Haemophilia Centres of The United Kingdom. Br Med J 1983; 286: 929-934
• 5 Rasi V, Ikkala E. Haemophiliacs with factor VIII inhibitors in Finland: incidence and outcome. Br J Haematol 1990; 76: 369-371
• 6 Tuddenham EGD, Cooper DN, Gitcher J. et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene. Nucleic Acids Research 1991; 19: 4821-4833
• 7 Miller DS, Steinbrecher RA, Wieland K. et al The molecular genetic analysis of Haemophilia A: characteristics of six partial deletions of the factor VIII gene. Hum Genet 1990; 86: 219-227
• 8 Antonarakis SE, Rossiter JP, Young M, Horst J, de Moerloose P. et al. Factor VIII gene inversion in severe hemophilia A: results of an international consortium study Blood 1995; 86 (06) 2206-2210
• 9 Frommel D, Allain JP, Saint-Paul E, Bosser C, Noel B, Mannucci PM, Pannicucci F, Blomback M, Prou Wartelle, Muller JY. HLA antigens and factor VIII antibody in classical hemophilia. Thromb Haemost 1981; 46: 687-689
• 10 Mayr WR, Lechner K, Neissner H, Papinger-Fashing I. HLADR and factor VIII antibodies in hemophilia A. Thromb Haemost 1984; 51: 293-296
• 11 Alper CAA, Raum DD, Awdeh ZL, Shapiro SS, Yunis EJ. Major Histocompatibility Complex (MHC)-linked complement alleles as markers for the development of anti-factor VIII in hemophiliacs Prog Clin Biol Res 1984; 150: 141-142
• 12 Aly AM, Aledort LM, Lee TD, Hoyer LW. Histocompatibility antigen patterns in haemophilic patients with factor VIII antibodies. Br J Haematol 1990; 76: 238-241
• 13 Papasteriades C, Varla M, Economidou J, Mitsouli C, Louiso UK, Manda-laki T, Roumelitou A, Papevangelou G. High frequency of HLADR5 in Greek patients with hemophilia A and hemophilia B Tissue antigens 1986; 28: 84-87
• 14 Lippert LE, McFisher A, Shook LB. Relationship of major histocompatibility complex class II genes to inhibitor antibody formation in hemophilia A Thrombosis and Haemostasis 1990; 91: 564-568
• 15 Lakich D, Kazazian HH, Antonarakis SE, Gitcher J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A Nature Genetics 1993; 5: 236-241
• 16 Doherty DG, Vaughan RW, Donaldson PT, Mowat AP, HLA DQA. DQB and DRB genotyping by oligonucleotide analysis: distribution of alleles and haplotypes in British Caucasoids Hum Immunol 1991; 34: 53-57
• 17 Tilikainen A, Lassus A, Karvonen J, Vartianen P, Julin M. Psoriasis and HLA-CW6 Br J Dermatol 1980; 102: 179-182
• 18 Brewerton DA, Caffrey M, Hart FD, James DCO, Sturrock RD. Ankylosing spondylitis and HLA-B27 Lancet 1973; 01: 904-907
• 19 Donn RP, Thompson W, Pepper L, Carthy D, Farhan A, Ryder C, South-wood T, Holt L, Ollier W. Br J Rheumatol 1995; 34: 461-465
• 20 Reveille JD, MacLeod MJ, Whittington K. et al. Specific amino acid residues in the second hypervariable region of HLA-DQA 1 and DQB1 chain genes promote the Ro (SS-A)/La(SS-B) autoantibody response. J Immunol 1991; 146: 3871-3876
• 21 Olsen ML, Arnett FC, Reveille JD. Contrasting molecular patterns of MHC class II alleles associated with the anti-SM and anti-RNP precipitin autoantibodies in systemic lupus erythematosus. Arthritis and Rheumatism 1993; 36: 090-104