Protection against anti–citrullinated protein antibody–positive rheumatoid arthritis is predominantly associated with HLA–DRB1*1301: A meta‐analysis of HLA–DRB1 associations with anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis in four European populations

Abstract

Objective. The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA.Methods. Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association.Results. In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

“…This is consistent with previous reports of a protective effect of *07 confined to Northern Europe, 47 perhaps due to unknown gene-environment interactions. The protective effect of D 70 was only observed in autoantibody-(RF and/ or ACPA) positive individuals, and a case-only analysis confirmed D 70 patients were less likely to be autoantibody positive (P ¼ 0.02).…”

“…58 HLA-DRB1*09 is also emerging as a risk allele in large Caucasian meta-analyses. 47 The current data provide independent confirmation of these HLA-DRB1 non-SE risk effects.…”

“…We found no evidence in support of previous suggestions that HLA-DRB1*13 accounts for the protective effect of DERAA against ACPA-positive RA. HLA-DRB1*13 is the commonest DERAA allele; perhaps, the removal of the HLA-DRB1*13 cases in the previous study 47 reduced its power to detect a DERAA effect.…”

“…42 Our finding that HLA-DRB1*0401 is more strongly associated with ACPA-positive RA than HLADRB1*0404 is consistent with most previous reports, 10,[43][44][45] although not all. 46 Subtle differences with other reports of a hierarchy of risk (*044*104*01) 47 may be attributed to differences in the genetic or environmental background, and/or to differences in statistical methods. Unlike some other European populations, 47 our data in common with other large cohorts 17 were consistent with a gene-dose effect of SE alleles, perhaps giving clues as to the role of HLA-DRB1 in RA pathogenesis.…”

“…46 Subtle differences with other reports of a hierarchy of risk (*044*104*01) 47 may be attributed to differences in the genetic or environmental background, and/or to differences in statistical methods. Unlike some other European populations, 47 our data in common with other large cohorts 17 were consistent with a gene-dose effect of SE alleles, perhaps giving clues as to the role of HLA-DRB1 in RA pathogenesis. We did not find an additional risk from HLA-DRB1*0401/*0404 compound heterozygosity in the sense of a greater than log-additive joint effect of the two alleles on risk.…”