Rheumatology Research Group, University of Birmingham, , Birmingham, UK.
Ann Rheum Dis. 2014 Apr;73(4):741-7. doi: 10.1136/annrheumdis-2012-202535. Epub 2013 Mar 16.
Data from North European rheumatoid arthritis (RA) populations has suggested a particularly strong association of gene-environment interaction between smoking and HLA-DRB1 shared epitope (SE) with antibodies to citrullinated α-enolase (CEP-1) and vimentin (cVim) peptides. We investigated this further by examining anticitrullinated peptide/protein antibody (ACPA) fine specificity in a Korean cohort, where there are notable differences in the RA-associated HLA-DRB1 alleles.
Antibodies to fibrinogen (cFib), α-enolase (CEP-1) and vimentin (cVim) peptides and cyclic citrullinated peptide (CCP) were measured in 513 cases. The Mann-Whitney U test was used to compare antibody levels. Logistic regression generated ORs for RA in a case-control analysis with 1101 controls. Association of ACPA status and erosion in patients with RA was examined by logistic regression.
Anti-CCP, CEP-1, cVim and fibrinogen peptides were found in 86.7%, 63.9%, 45.5% and 74.7%, respectively. The number of ACPA and their levels were associated with SE, with evidence of a gene-dosage effect. There was a particular association of smoking with levels of anti-CEP-1. However, a gene-environment interaction was associated with all the ACPA positive subgroups, albeit the highest OR was seen with the anti-CCP+/cVim+ subset. In the absence of SE, smoking only conferred risk for anti-CCP negative subsets. The presence of erosions was not associated with the number of positive ACPA or specificity.
The SE governed the magnitude and diversity of the ACPA response, but its interaction with smoking did not exclusively segregate with any of the ACPA specificities studied here. Smoking was associated with RA by SE-dependent and independent effects.
北欧类风湿关节炎（RA）人群的数据表明，吸烟与 HLA-DRB1 共享表位（SE）之间的基因-环境相互作用与抗瓜氨酸化α-烯醇酶（CEP-1）和波形蛋白（cVim）肽抗体之间存在特别强的关联。我们通过检查韩国队列中的抗瓜氨酸肽/蛋白抗体（ACPA）的精细特异性进一步研究了这一点，在韩国队列中，RA 相关的 HLA-DRB1 等位基因存在显著差异。
在 513 例病例中测量了纤维蛋白原（cFib）、α-烯醇酶（CEP-1）和波形蛋白（cVim）肽和环瓜氨酸肽（CCP）的抗体。使用 Mann-Whitney U 检验比较抗体水平。在病例对照分析中，使用逻辑回归生成了与 1101 名对照相比 RA 的 OR。通过逻辑回归检查 RA 患者的 ACPA 状态与侵蚀之间的关联。
分别发现 86.7%、63.9%、45.5%和 74.7%的患者存在抗 CCP、CEP-1、cVim 和纤维蛋白原肽。ACPA 的数量及其水平与 SE 相关，存在基因剂量效应的证据。吸烟与抗 CEP-1 水平之间存在特定关联。然而，基因-环境相互作用与所有 ACPA 阳性亚组相关，尽管与抗 CCP+/cVim+亚组的最高 OR 相关。在没有 SE 的情况下，吸烟仅会导致抗 CCP 阴性亚组的风险增加。存在侵蚀与阳性 ACPA 的数量或特异性无关。
SE 决定了 ACPA 反应的幅度和多样性，但它与吸烟的相互作用并非仅与我们在此处研究的任何 ACPA 特异性相关。吸烟通过 SE 依赖性和非依赖性效应与 RA 相关。
