Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins
Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins
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DOI：
10.1002/art.21385
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发表时间：
2005-11-01
影响因子：
--
通讯作者：
Criswell, LA
中科院分区：
文献类型：
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作者：
Huizinga, TWJ;Amos, CI;Criswell, LA
目标。类风湿关节炎（RA）的主要遗传危险因素，HLA区域，已经被发现了25年。先前的研究表明，在RA人群中，携带共享表位（SE）的HLA-DRB1等位基因与针对环瓜氨酸肽的抗体（抗ccp抗体）之间存在关联。我们进行这项研究是为了首次比较健康人群中SE等位基因频率与携带或不携带抗ccp抗体的RA患者的等位基因频率。HLA-DRB1分型研究对象为来自莱顿早期关节炎诊所（Leiden Early Arthritis Clinic, Leiden EAC）的408名RA患者，423名健康的荷兰对照，以及来自北美RA联盟（NNRAC）的341名美国多重（兄弟姐妹）高加索家族的720名患病成员，这些患者的疾病已经确立，并符合美国风湿病学会的RA分类标准。酶联免疫吸附法检测抗ccp抗体的存在。对于Leiden EAC，描述2拷贝SE等位基因与抗ccp阳性（以健康对照组无拷贝SE等位基因为参照）相关的比值比（OR）为11.79 (P < 0.0001)，而1拷贝SE等位基因的OR为4.37 （P < 0.0001）。荷兰抗ccp阴性RA患者与SE无关联。对于NARAC家族，连锁和关联分析显示SE仅与抗ccp阳性疾病相关，而与抗ccp阴性疾病无关。分层分析表明，抗ccp抗体主要介导SE与关节损伤或疾病持续存在的关联。编码SE的HLA-DRB1等位基因对于以瓜氨酸化肽抗体为特征的疾病是特异性的，这表明这些等位基因与RA并不相关，而是与特定的表型相关。
Objective. The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies.Methods. HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NNRAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay.Results. For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence.Conclusion. HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.