Abstract

We read with great interest the editorial by Bridges and coworkers (1) commenting on the various HLA shared epitope (SE) classification systems and their merits and weaknesses. We agree with their comment that alternative classifications of the SE will increase our insight into the role of HLA–DRB1 alleles in rheumatoid arthritis (RA), but, in contrast to the suggestion made by those authors, we believe relevant insights also can be obtained by analyzing the HLA alleles that confer protection against disease. Bridges and colleagues question the findings that particular HLA–DRB1 alleles are protective against RA, arguing that “if there is enrichment of SE-containing alleles among patients compared with controls, there must be a corresponding depletion of some alleles among controls as compared with patients. If, in conjunction with the enrichment of SE-containing alleles, there are particular alleles whose frequencies are consistently diminished, then it is impossible to determine whether the affected population has an overrepresentation of a risk allele or an underrepresentation of a ‘protective’ allele.” This would be analogous to tic-tac-toe as, in order for one player to win this game, the other must lose. However, the HLA system is much more complex than tic-tac-toe, and solutions to handle such complexities have been published previously (2). These rely on the fact that HLA genes, such as DRB1, are not diallelic, and one can therefore perform stratifications for known associations. For example, we have described protective effects of particular HLA molecules bearing the amino acid sequence DERAA (DRB1*0103,*0402,*1102,*1103,*1301,*1302,*1304) (3). Since we wondered whether the effect of the DERAA-encoding alleles is truly protective or is the result of the concomitant absence of predisposing SE alleles (as would be the case in tic-tac-toe), we determined the effect of the DERAA-encoding alleles both in subjects without SE alleles and, in a separate analysis, in patients with 1 SE allele (3). These data revealed that individuals carrying 1 SE allele and 1 DERAA allele have a lower risk of RA and experience a less severe disease course than individuals with 1 SE allele and 1 “X” allele (where “X” = non-SE, non-DERAA alleles). Similarly, subjects carrying 1 “X” allele and 1 DERAA allele were less predisposed to RA than were subjects with 2 “X” alleles. As such, the comparison of subgroups allowed differentiation of the effects of protection and non-predisposition. These observations were confirmed in an analysis of the influence of DERAA-encoding HLA alleles on RA susceptibility in a family-based study (4). Similar protective effects have also been described by others, using a different classification system (5, 6). As it is currently not clear which model best fits with the protective effects observed in different studies, it remains to be determined which particular HLA alleles confer protection against which phenotype of disease. However, our data (3) clearly demonstrate that, by stratification for the presence or absence of the “risk allele,” possible protective effects associated with other HLA alleles can become apparent, which cannot be explained by lessons learned from tic-tac-toe. While clustering HLA alleles to find common themes that could explain the HLA–RA association could be rewarding, another challenge of the research into the connection between the HLA system and RA is found in determining the biologic pathways underlying this association. Information obtained from different models involving clustering of a mixture of (diverse) HLA haplotypes associated with either protection or susceptibility could be helpful in guiding the way to the design of novel theories and experiments aimed at understanding the contribution of the HLA system to RA. A. H. M. van der Helm-van Mil MD, PhD*, T. W. J. Huizinga MD*, R. R. P. de Vries MD, PhD*, R. E. M. Toes PhD*, * Leiden University Medical Center, Leiden, The Netherlands.

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