Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis patients

Abstract

Objective: The strongest known genetic association in rheumatoid arthritis (RA) is with HLA-DRB1 alleles that share a similar amino acid sequence, termed the shared epitope (SE). Although many studies have examined the association of the SE with disease severity, the results have been inconsistent, which may reflect the relatively small sample sizes or ethnic differences. The aim of this study was to assess the association of HLA-DRB1 SE alleles and genotype with the development of bony erosions in RA by meta-analysis.

Methods: We identified English-language articles published between January 1, 1987 and June 1, 1999 through Medline, EMBase, and manual searches of 6 relevant journals. Included were studies in which molecular typing of HLA-DRB1 alleles was performed and in which the presence or absence of bony erosions was reported. Data were extracted from the studies, and erosions were coded as present or absent. Authors were contacted for missing information and data on individual patients.

Results: A total of 29 studies and 3,240 patients were available for analysis. The summary odds ratios (ORs), when all patients were evaluated as a single group, demonstrated a significant association of the presence of the SE (2 or 1 versus 0 SE alleles) with erosions (OR 2.0; 95% confidence interval [95% CI] 1.8-2.2), although significant heterogeneity was present (P = 0.002). Subgroup analyses demonstrated the important influence of ethnic background. For example, no association of the SE with erosions was demonstrated in Greeks (OR 0.8 [95% CI 0.2-1.5]). In contrast, there was a striking dose-dependent relationship in southern European Caucasians and Asians, with ORs as high as 6.2 and 5.4, respectively, in patients with 2 SE alleles. Although our ability to assess the relationship between SE genotype and erosions was limited, particular importance of the DRB1*0401 SE allele was suggested in an analysis restricted to northern European Caucasians.

Conclusion: The SE is associated with the development of erosive disease in many ethnic groups; however, striking exceptions exist. These variations may be due to allele differences between populations, such as the frequency of DRB1*0401 among different ethnic groups. Further study to better understand the genetic and environmental differences between these populations may provide insight into mechanisms that influence the clinical expression of RA.