From the Department of Rheumatology and Clinical Immunology, and the Center for Genomic Medicine, Graduate School of Medicine, and the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto; Institute of Rheumatology, Tokyo Women's Medical University, Tokyo; Aichi Cancer Center Hospital and Research Institute, Nagoya; HLA Laboratory, Kyoto; Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan; Division of Rheumatology, Immunology, and Allergy, and the Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
R. Hiwa, MD, Research student, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University; K. Ikari, MD, PhD, Associate professor, Institute of Rheumatology, Tokyo Women's Medical University; K. Ohmura, MD, PhD, Associate professor, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University; S. Nakabo, MD, Research student, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University; K. Matsuo, MD, PhD, Chief, Aichi Cancer Center Hospital and Research Institute; H. Saji, PhD, Director, HLA Laboratory; K. Yurugi, Chief, Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital; Y. Miura, MD, PhD, Assistant professor, Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital; T. Maekawa, MD, PhD, Professor, Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital; A. Taniguchi, MD, PhD, Professor, Institute of Rheumatology, Tokyo Women's Medical University; H. Yamanaka, MD, PhD, Professor, Institute of Rheumatology, Tokyo Women's Medical University; F. Matsuda, PhD, Professor, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University; T. Mimori, MD, PhD, Professor, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University; C. Terao, MD, PhD, Assistant professor, Center for Genomic Medicine, Graduate School of Medicine, and the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, and the Division of Rheumatology, Immunology, and Allergy, and Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, and Program in Medical and Population Genetics, Broad Institute.
J Rheumatol. 2018 Apr;45(4):470-480. doi: 10.3899/jrheum.170363. Epub 2018 Feb 1.
is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF.
A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF- subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions.
RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF- showed similar genetic associations to ACPA+ and ACPA- RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70).
The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.
是与类风湿关节炎 (RA) 和抗瓜氨酸化蛋白抗体 (ACPA) 关联最密切的基因座。然而，RA 病程中类风湿因子 (RF) 的波动使得根据 RF 阳性的一致性来定义亚组变得困难，因为这会影响到对遗传背景和 RF 水平的分析。
共纳入 2873 例 RA 患者和 2008 例健康对照者。我们对参与者进行了 HLA-DRB1 等位基因分型，并收集了病例组中 RF 的连续数据。除了 RF+和 RF-亚组外，我们还将 RF+患者分为组 1（持续 RF+）和组 2（血清转换）。我们比较了 RA 亚组和对照组之间的 HLA-DRB1 等位基因，并进行线性回归分析以确定与最大 RF 水平相关的 HLA-DRB1 等位基因。我们进行了整体检验来评估重要的氨基酸位置。
RF 阳性率为 88%，1372 例和 970 例 RF+患者分别归入组 1 和组 2。RF+和 RF-分别与 ACPA+和 ACPA-RA 具有相似的遗传关联。我们发现共享表位 (SE) 在组 2 中比组 1 更为丰富，p=2.0×10，并且在位置 11 上的氨基酸显示出 1 与 2 之间的显著关联，p=2.7×10。这些关联与 ACPA 阳性无关。SE 与 RF 滴度呈负相关趋势（p=0.012）。降低 ACPA 滴度的 HLA-DRB1*09:01 与 RF 水平无关（p=0.70）。
血清转换组表现出独特的遗传特征。RF 水平的遗传结构与 ACPA 不同。
