A majority of Brazilian patients with rheumatoid arthritis HLA-DRB1 alleles carry both the HLA-DRB1 shared epitope and anti-citrunillated peptide antibodies

P Louzada-Júnior,N.H.S Deghaide,R.D.R Oliveira,M.B Bertolo,R.A Conde,E.A Donadi,M.V.C Freitas

doi:10.1590/s0100-879x2008005000021

Abstract

The objective of the present study was to evaluate the contribution of the shared epitope (SE), the rheumatoid arthritis (RA) protection model, and the occurrence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in RA patients from a genetically diverse population. One hundred and forty Brazilian RA patients and 161 matched controls were typed for HLA-DRB1 alleles using amplified DNA hybridized with sequence-specific oligonucleotide probes or primers. Patients were stratified according to the presence or absence of SE (DRB1*0401, *0404, *0405, *0101, *1001, and *1402), of the DERAA alleles (DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304), and X (all other alleles). Anti-CCP antibodies were measured by ELISA. The combined frequency of SE-positive alleles was significantly greater (76.4 vs 23.6%, P < 0.0001) than the controls. The SE/SE and SE/X genotypes were over-represented (P < 0.0001, OR = 6.02) and DERAA/X was under-represented in RA patients (P < 0.001, OR = 0.49), whereas the frequencies of the SE/DERAA, X/X and X/DERAA genotypes were not significantly different from controls. The frequency of anti-CCP antibodies was higher in SE-positive patients than in SE-negative patients (64.6 vs 44.7%, P = 0.03; OR = 2.25). Although the Brazilian population is highly miscegenated, the results of this study support the findings observed in most genetically homogeneous populations with RA; however, they are not mutually exclusive but rather complementary. The participation of DRB1-DERAA alleles in protection against RA was also observed (OR = 0.4; 95%CI = 0.23-0.68).

Highlights

Several lines of evidence indicate the role of major histocompatibility complex class II molecules in the susceptibility to seropositive rheumatoid arthritis (RA), the molecules encoded by human leukocyte antigen (HLA)-DRB1 genes [1]
Brazilian Amerindian populations still exist as semi-isolated tribal groups, but their genes are represented in modern urban populations
Since the DRB1*04, *01 and *10 allelic frequencies are different for White and Black individuals, Pina et al performed a study on RA patients using exclusively AfroBrazilian descendants (Pina FP, Conde RC, LouzadaJúnior P, Donadi EA, Bertolo MB, unpublished data)

Summary

Introduction

Several lines of evidence indicate the role of major histocompatibility complex class II molecules in the susceptibility to seropositive rheumatoid arthritis (RA), the molecules encoded by HLA-DRB1 genes [1]. In addition to the association of RA and SE-positive (SE+) alleles, SE-negative (SE-) alleles are reported to influence susceptibility to RA by means of particular polymorphic anchor residue sequences present in one of the 5 peptide-binding pockets of the DRß1 chain, i.e., pockets 1, 4, 6, 7, and 9 (P1, P4, P6, P7, and P9). These pockets may influence the peptide-binding specificity of human leukocyte antigen (HLA) class II molecules, P4 [12]. Alleles that possess a positive electric charge in their P4, such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 alleles, have no influence on predisposition to RA [12,13]

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