Mitsunaga S, Suzuki Y, Kuwana M, Sato S, Kaneko Y, Homma Y, Narita A, Kashiwase K, Okudaira Y, Inoue I, Kulski J K, Inoko H
Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Tissue Antigens. 2012 Jul;80(1):16-25. doi: 10.1111/j.1399-0039.2012.01872.x. Epub 2012 Apr 4.
Although the HLA region contributes to one-third of the genetic factors affecting rheumatoid arthritis (RA), there are few reports on the association of the disease with any of the HLA loci other than the DRB1. In this study we examined the association between RA and the alleles of the six classical HLA loci including DRB1. Six HLA loci (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) of 1659 Japanese subjects (622 cases; 488 anti-cyclic citrullinated peptides (CCP) antibody (Ab) positive (82.6%); 103 anti-CCP Ab negative (17.4%); 31 not known and 1037 controls) were genotyped. Disease types and positivity/negativity for CCP autoantibodies were used to stratify the cases. Statistical and genetic assessments were performed by Fisher's exact tests, odds ratio, trend tests and haplotype estimation. None of the HLA loci were significantly associated with CCP sero-negative cases after Bonferroni correction and we therefore limited further analyses to using only the anti CCP-positive RA cases and both anti-CCP positive and anti-CCP negative controls. Some alleles of the non-DRB1 HLA loci showed significant association with RA, which could be explained by linkage disequilibrium with DRB1 alleles. However, DPB102:01, DPB104:01 and DPB109:01 conferred RA risk/protection independently from DRB1. DPB102:01 was significantly associated with the highly erosive disease type. The odds ratio of the four HLA-loci haplotypes with DRB104:05 and DQB104:01, which were the high-risk HLA alleles in Japanese, varied from 1.01 to 5.58. C07:04, and B15:18 showed similar P-values and odds ratios to DRB1*04:01, which was located on the same haplotype. This haplotype analysis showed that the DRB1 gene as well as five other HLA loci is required for a more comprehensive understanding of the genetic association between HLA and RA than analyzing DRB1 alone.
尽管人类白细胞抗原（HLA）区域对影响类风湿性关节炎（RA）的遗传因素贡献了三分之一，但除了DRB1之外，关于该疾病与任何HLA基因座关联的报道很少。在本研究中，我们检测了RA与包括DRB1在内的六个经典HLA基因座的等位基因之间的关联。对1659名日本受试者（622例患者；488例抗环瓜氨酸肽（CCP）抗体（Ab）阳性（82.6%）；103例抗CCP Ab阴性（17.4%）；31例情况不明；1037例对照）的六个HLA基因座（HLA - A、- B、- C、- DRB1、- DQB1和 - DPB1）进行了基因分型。根据疾病类型和CCP自身抗体的阳性/阴性对病例进行分层。通过Fisher精确检验、优势比、趋势检验和单倍型估计进行统计和遗传评估。在Bonferroni校正后，没有一个HLA基因座与CCP血清阴性病例显著相关，因此我们将进一步分析仅限于仅使用抗CCP阳性的RA病例以及抗CCP阳性和抗CCP阴性对照。非DRB1的HLA基因座的一些等位基因显示与RA有显著关联，这可以通过与DRB1等位基因的连锁不平衡来解释。然而，DPB102:01、DPB104:01和DPB109:01独立于DRB1赋予RA风险/保护作用。DPB102:01与高度侵蚀性疾病类型显著相关。在日本人中作为高风险HLA等位基因的带有DRB104:05和DQB104:01的四个HLA基因座单倍型的优势比在1.01至5.58之间变化。C07:04和B15:18显示出与位于同一单倍型上的DRB1*04:01相似的P值和优势比。这种单倍型分析表明，与单独分析DRB1相比，为了更全面地理解HLA与RA之间的遗传关联，需要DRB1基因以及其他五个HLA基因座。
