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Human proteome and hemophilia A inhibitor risk
Results
An example of proteome cross-matching
Arg593Cys (R593C) (R612C using Human Genome Variation Society numbering) is a relatively common F8 missense mutation that has been identified as being asso- ciated with an “increased” risk of inhibitor formation – for example, 12/106 (11.3%) of R593C individuals in the INSIGHT cohort have been reported as having an inhibitor.8 Taking the common HLA-DR allele HLA- DRB1*01:01 as an example, our analysis of predicted inhibitor risk proceeded as follows.
of the tFVIII 15-mers spanning position 593 are binders. Several such 15-mers were predicted to bind to the MHC molecule associated with HLA-DRB1*01:01, and some had binding cores that span position R593. There were two such cores – IQRFLPNPA and YLTENIQRF – both of which were associated with multiple binding peptides, as shown in Figure 3A.
The next step assessed whether either of these cores was associated with predicted pMHC surface novelty compared to their respective endogenous counterparts. Both of the endogenous cores – IQCFLPNPA and YLTENIQCF, respectively [with a Cys (C) in place of the Arg (R) of the equivalent tFVIII peptides] – were associat-
A
We began by using NetMHCII20 to predict whether any
B
Figure 3. An example of information peptide- MHC binding and novel surface: Arg593Cys for HLA-DRB1*0101. (A) NetMHCII predicts there are binding tFVIII 15-mers that have two cores – IQRFLPNPA and YLTENIQRF – containing Arg593 (R593). (B) These two cores form pMHC sur- faces that are novel compared to the equivalent surfaces for endogenous FVIII. FVIII: factor VIII; tFVIII: therapeutic factor VIII; MHC: major histo- compatibility complex; pMHC: peptide-major his- tocompatibility complex.
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