van der Woude Diane, Lie Benedicte A, Lundström Emeli, Balsa Alejandro, Feitsma Anouk L, Houwing-Duistermaat Jeanine J, Verduijn Willem, Nordang Gry B N, Alfredsson Lars, Klareskog Lars, Pascual-Salcedo Dora, Gonzalez-Gay Miguel A, Lopez-Nevot Miguel A, Valero Fernando, Roep Bart O, Huizinga Tom W J, Kvien Tore K, Martín Javier, Padyukov Leonid, de Vries René R P, Toes René E M
Leiden University Medical Center, Leiden, The Netherlands.
Arthritis Rheum. 2010 May;62(5):1236-45. doi: 10.1002/art.27366.
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.
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.
In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB113 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 DRB113 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB113, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB113 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles.
Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301.
人们对HLA - DRB1等位基因对类风湿关节炎（RA）发病的保护作用了解甚少。本研究旨在对4个欧洲人群进行荟萃分析，以调查哪些HLA - DRB1等位基因与抗瓜氨酸化蛋白抗体（ACPA）阳性RA和ACPA阴性RA的保护作用相关。
从挪威、瑞典、荷兰和西班牙这4个欧洲国家收集了超过2800例患者和超过3000例对照受试者的HLA - DRB1分型及ACPA状态信息。在一项聚焦于保护等位基因和分类的联合荟萃分析中，分析了与不同HLA - DRB1等位基因相关的比值比（OR）和95%置信区间（95%CI）。对ACPA阳性RA的分析按共享表位（SE）等位基因进行分层，以校正由于这种关联导致的偏差。
在ACPA阳性RA中，经SE分层后唯一具有保护作用的等位基因是HLA - DRB113等位基因（OR 0.54 [95%CI 0.38 - 0.77]）。排除DRB113后，基于DERAA和D70序列的等位基因分类的保护作用不再存在（对于D70，OR 0.97 [95%CI 0.75 - 1.25]），这表明与保护作用相关的是DRB113，而非DERAA或D70序列本身。在DRB113等位基因中, 只有DRB1*1301与保护作用相关（OR 0.24 [95%CI 0.09 - 0.59]）。保护作用似乎呈现出从北到南的梯度，在北欧国家关联最强。在ACPA阴性RA中，与HLA - DRB1等位基因没有显著关联。
我们的数据不支持任何保护等位基因的分类，并表明对ACPA阳性RA的保护作用主要与HLA - DRB1*1301相关。
