Laki Judit, Lundström Emeli, Snir Omri, Rönnelid Johan, Ganji Izabella, Catrina Anca I, Bengtsson Camilla, Saevarsdottir Saedis, Wick Marius C, Alfredsson Lars, Klareskog Lars, Padyukov Leonid
Karolinska Institutet, Stockholm, Sweden.
Arthritis Rheum. 2012 Jul;64(7):2078-84. doi: 10.1002/art.34421.
Production of anti-citrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLA-DRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA.
HLA-DRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients.
No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLA-DRB115 allele was associated with high ACPA levels (P=0.0002). A similar trend was detected in HLA-DRB115-positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLA-DRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P<0.0001 by Mantel-Haenszel test with a fixed-effects model).
Our data indicate that HLA-DRB115 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLA-DRB115 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.
抗瓜氨酸化蛋白抗体（ACPA）的产生是类风湿关节炎（RA）的一项重要生物标志物。我们开展本研究以确定遗传因素（HLA - DRB1等位基因）是否与ACPA阳性RA患者的ACPA极端水平相关，并确定这些RA亚组是否存在任何相关的表型特征。
对来自瑞典类风湿关节炎流行病学调查研究的1073例ACPA阳性RA患者进行HLA - DRB1等位基因组分型。我们发现283例患者（26.4%）ACPA水平高（使用欧洲诊断公司抗CCP2检测定义为>1500单位/毫升），其余患者ACPA水平中等并作为对照组。一个复制组由235例RA患者组成。
ACPA水平高的患者与ACPA水平中等的患者在基线疾病活动度方面未观察到显著差异。然而，HLA - DRB115等位基因与ACPA高水平相关（P = 0.0002）。在复制队列中HLA - DRB115阳性患者中检测到类似趋势，对发现队列和复制队列进行荟萃分析表明，HLA - DRB1*15对发现队列和复制队列中ACPA高水平的发生均有总体影响（采用固定效应模型的Mantel - Haenszel检验，P<0.0001）。
我们的数据表明HLA - DRB115可能促进ACPA高水平的产生。由于ACPA水平评分在2010年美国风湿病学会/欧洲抗风湿病联盟RA分类标准中具有很高价值，HLA - DRB115的存在可能至少部分有助于满足RA的标准。这说明了ACPA水平遗传调控的复杂性。关于ACPA和ACPA阳性RA调控的更多机制研究尚待进行。
