Abstract
In hemophilia A (HA) patients, F8 gene-defects as genetic risk-factors for developing inhibitors to Factor VIII have been extensively studied. Here we provide estimates of inhibitor-risk associated with the patient's Human Leukocyte Antigen (HLA). We used next generation sequencing for high-resolution HLA Class II typing of 997 HA patients. Using inhibitor prevalence reports from the My Life Our Future (MLOF) research repository, we calculated Odds Ratios (OR) for inhibitor development in a multivariate model considering HLA-DRB1/3/4/5, HLA-DPB1, HLA-DQB1, race, F8 pathogenic variant type, and age. Participants with 1 HLA variant (DPB1*02:02) had developed inhibitors at a higher rate while participants with 2 HLA variants (DRB1*04:07; DRB1*11:04) had developed inhibitors at a lower rate. Additionally, patients with missense variants had developed inhibitors at a lower rate and participants with large structural changes (>50 bp) had developed inhibitors at a higher rate (both compared to Intron 22 inversion). Using a cohort of participants with a distribution of HLA-DRB1 alleles comparable to that in the North American population we show that the HLA repertoire of a HA patient can be a risk-factor for inhibitor development.
Highlights
An unmet need in the management of hemophilia-A (HA) is the lack of clinically validated markers associated with the development of inhibitors, i.e., neutralizing antibodies to Factor VIII (FVIII)
We have presented a detailed breakdown of participant characteristics for the entire ATHNdataset (N = 7,151), The subset of human leukocyte antigens (HLA)-typed participants with Severe HA (N = 612), and the HLA-typed subset (N = 997) (Tables 1–3)
We have compared the characteristics of the HLA-type group as a whole with the entire ATHNdataset to ensure that there was no bias in the cohort selection other than the enrichment of inhibitor positive cases (Supplementary Table 1)
Summary
An unmet need in the management of hemophilia-A (HA) is the lack of clinically validated markers associated with the development of inhibitors, i.e., neutralizing antibodies to Factor VIII (FVIII). There have been several studies to identify HLA variants potentially associated with inhibitors, no consistent correlates were found between studies [10,11,12,13,14] These studies were all performed with small sample sizes ranging from 57 to 176 participants. An earlier meta-analysis (of 30 independent studies and 5,383 participants) showed that larger gene disruptions (e.g., deletion of multiple exons) were associated with a higher OR of developing inhibitors [5]. As the MLOF collaboration did not HLA type the participants, we have HLA typed 1,000 participants for whom F8 genotype and clinical and demographic information was available This data set is at least four-times larger than those used in published studies and is adequate to assess the association between HLA type and inhibitors. We show that Hispanic participants had a higher prevalence of inhibitors
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