HLA-DRB1 alleles encoding the shared epitope (SE) are associated with rheumatoid arthritis (RA) but the underlying biological mechanism is unknown. Several case–control studies have been published on the protective effect of particular SE negative alleles, according to the physicochemical properties of the fourth antigenic peptide binding pocket (P4). The present study was undertaken to test those hypotheses taking advantage of a familial based association analysis.

One hundred French Caucasian families with one RA patient and both parents were genotyped for HLA-DRB1. The analysis relied on the allelic frequency calculation, the transmission disequilibrium test (TDT) and the genotype relative risk analysis (GRR).

After the demonstration of the association of SE with RA in our sample (P = 4.8 × 10^-14), we replicated the strong protective effect of HLA-DRB1*1501 alleles (P = 4.77 × 10^-7). We also replicated a protective effect against RA of the alleles with an isoleucine at position 67 (P = 1.93 × 10^-5) and the alleles with an aspartic acid at position 70 (P = 3 × 10^-3). We failed to replicate any protective effect of the alleles with a neutral or negative electric charge of the P4 pocket, nor a modulation of SE effect by those alleles. We also failed to replicate the protective effect of Q and De alleles according to the functional categorization of HLA-DRB1 alleles.

Our findings are in keeping with a protective effect against RA of SE negative alleles (HLA-DRB1*1501, alleles with an isoleucine at position 67 and alleles with an aspartic acid at position 70).