Influence of HLA-DRB1 P4 binding pocket electric charge on rheumatoid arthritis (RA) susceptibility

Background

HLA-DRB1 alleles coding for the shared epitope (SE), an amino acid motif in the third hypervariable region of the beta 1 chain of HLA-DR, are associated with RA. The underlying biological mechanism is unknown. A model was recently proposed (Reviron et al. Arthritis Rheum 2001; 44:535–540), based on the electric charge (EC) of the fourth antigenic peptide-binding pocket (P4) of the HLA-DR molecule. SE alleles carrying a strong positive EC at P4, the model postulates that the negative EC of the P4 has a protective effect for RA that modulates the effect of the SE.

Objective

To test that model, taking advantage of familial-based association analysis.

Methods

The DNA of 100 Caucasian French families with one RA patient and both parents were genotyped for HLA-DRB1. Genotypes were stratified in susceptible (S), neutral (N) and protective (P) groups: S for the genotype SE/SE and the genotype SE/EC⁺ (non SE allele with a positive EC); N for the genotype SE/EC^- (non SE allele with a negative EC) and the genotype EC⁺/EC⁺; P for the genotype EC^-/EC^- and the genotype EC^-/EC⁺.

The analysis was performed with a genotype relative-risk method comparing the RA patient genotypes with the virtual control genotypes reconstructed from parental untransmitted alleles. The expectations from the model were: S genotype more frequent in RA, N genotype with similar frequency in RA and controls and P genotype more frequent in controls.

Results

The S genotype was more frequent in RA (55% versus 29%, P = 1.9 × 10^-4), the N genotype had similar frequencies (33% in RA versus 29% in controls, not significant) and the P genotype was more frequent in controls (42% versus 12%, P = 1.8 × 10^-6).

Conclusion

Our results are in keeping with a protective effect of the negative EC of the P4 HLA-DR pocket modulating the SE effect on RA susceptibility.