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.
