Laboratory of Immunology, 3rd Department of Medicine, University of Debrecen Medical and Health Science Center, 98 Nagyerdei street, Debrecen, H-4012, Hungary.
Rheumatology (Oxford). 2010 Jan;49(1):25-33. doi: 10.1093/rheumatology/kep338. Epub 2009 Nov 17.
HLA-DR [shared epitope (SE)] alleles have recently been re-classified into S1, S2, S3P and S3D groups. S2 and S3P have been associated with increased risk for RA. We assessed the impact of S1, S2, S3P and S3D alleles on anti-citrullinated protein antibody (ACPA) production. Instead of comparing allele-carriers to non-carriers, we studied each allele group individually, using the X/X (non-SE) genotype as reference.
Serum and genomic DNA samples of 91 RA patients and 78 healthy controls were obtained. Various ACPAs and IgM RF were determined by ELISA. HLA-DRB1 genotyping and subtyping was performed by PCR. HLA-DRB1 alleles were re-classified as described above. Correlations between SE and ACPAs were determined.
Not only S2 and S3P, but, to a lesser extent, S1 and S3D alleles also predisposed to anti-cyclic citrullinated peptide (CCP) production (P < 0.0001, P = 0.004, P = 0.01 and P = 0.027, respectively), with the following hierarchy of association: S2+S3P > S1+S3D > X/X. Similar associations were observed for anti-citrullinated vimentin. Anti-citrullinated fibrinogen (CF) exerted a different association pattern with the strongest correlation with S1 alleles [odds ratio (OR) 16.00; P = 0.05]. In addition, HLA-DRB115 alleles may represent a special predisposing effect for anti-CF antibody production. Finally, in this study, RF production was associated only with the HLA-DRB10401 SE allele (P = 0.04).
Our approach of comparing individual S allele carriers with X/X genotype patients allowed us to perform unequivocal analyses and demonstrate new associations. Thus, novel subgroups of RA could be identified with potential relevance for prognosis and therapy.
HLA-DR [共享表位（SE）] 等位基因最近被重新分类为 S1、S2、S3P 和 S3D 组。S2 和 S3P 与 RA 风险增加有关。我们评估了 S1、S2、S3P 和 S3D 等位基因对抗瓜氨酸化蛋白抗体（ACPA）产生的影响。我们没有将等位基因携带者与非携带者进行比较，而是单独研究每个等位基因组，以 X/X（非 SE）基因型作为参考。
收集 91 例 RA 患者和 78 例健康对照者的血清和基因组 DNA 样本。通过 ELISA 测定各种 ACPA 和 IgM RF。通过 PCR 进行 HLA-DRB1 基因分型和亚型分析。如上所述，将 HLA-DRB1 等位基因重新分类。确定 SE 与 ACPA 之间的相关性。
不仅 S2 和 S3P，而且程度较轻的 S1 和 S3D 等位基因也容易产生抗环瓜氨酸肽（CCP）（P<0.0001，P=0.004，P=0.01 和 P=0.027），其关联顺序为：S2+S3P>S1+S3D>X/X。类似的关联也见于抗瓜氨酸波形蛋白。抗瓜氨酸纤维蛋白原（CF）的相关性不同，与 S1 等位基因相关性最强[比值比（OR）16.00；P=0.05]。此外，HLA-DRB115 等位基因可能代表抗 CF 抗体产生的特殊易感性。最后，在这项研究中，RF 产生仅与 HLA-DRB10401 SE 等位基因相关（P=0.04）。
我们比较单个 S 等位基因携带者与 X/X 基因型患者的方法使我们能够进行明确的分析，并证明了新的关联。因此，可能与预后和治疗相关的新的 RA 亚组可以被识别。
