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Human proteome and hemophilia A inhibitor risk
inhibitor formation is largely HLA-dependent and, in most cases, cannot be reliably predicted from knowledge of the F8 genotype alone. The proportion of reported F8 mis- sense mutations that we predict to be risk-associated varies considerably between different HLA isoforms. For example, with a binding threshold of 1000 nM, it ranges between 21% (HLA-DQA1*03:01-DQB1*03:02 and HLA- DQA1*04:01-DQB1*04:02) to 86% (HLA-DRB1*01:01) without proteome cross-matches, and between 13% (HLA-DQA1*04:01-DQB1*04:02) and 48% (HLA-
A
DRB1*01:01) with proteome cross-matches. Values for all 25 HLA isoforms and multiple binding thresholds are given in Online Supplementary Table S2. The number of F8 missense mutations associated with no, or negligible, pre- dicted risk (black columns in the heatmap) is only 69 out of 956 (7%).
We consider any (human) protein that, in effect, con- tributes to a reduction in predicted inhibitor risk for one or more F8 missense mutation/HLA isoform combinations to be “protective”. Of the 20,300 proteins in the human pro-
B
Figure 5. MHC-binding strengths of F8 peptides predicted to form novel pMHC surfaces with and without proteome scanning. Heatmap showing the predicted occurrence of novel pMHC surfaces and binding strengths for 25 HLA-DR/DP/DQ isoforms (y axis) covering the first 50 missense mutations in the Factor VIII Gene (F8) Variant Database (x axis). Black and gray squares indicate F8 missense mutation/HLA isoform combinations that are not predicted to form a novel pMHC sur- face. Otherwise the temperature color scale indicates the predicted binding strength of the strongest binding peptide with a novel pMHC surface for each remaining F8 missense mutation/HLA isoform combination. The full heatmap for all missense F8 mutations is given in Online Supplementary Figure S1. (A) MHC-binding strengths of F8 peptides predicted to form novel pMHC surfaces (colored squares), or not (black squares), without proteome scanning. (B) MHC-binding strengths of F8 peptides predicted to form novel pMHC surfaces with proteome scanning. Gray squares indicate F8 missense mutation/HLA isoform combinations that are no longer predicted to form a novel pMHC surface after cross-matches to the proteome are taken into account. MHC: major histocompatibility complex; pMHC: peptide- major histocompatibility complex; HLA: human leukocyte antigen.
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