Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Clinical Research Center, Shizuoka General Hospital, Shizuoka 420-8527, Japan; The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
Department of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Solna, 171 76 Stockholm, Sweden; Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden.
Am J Hum Genet. 2019 Sep 5;105(3):616-624. doi: 10.1016/j.ajhg.2019.08.002. Epub 2019 Aug 29.
Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (B) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(-) RA-affected case subjects separately. In CCP2(-) RA, we observed that the association between CCP2(-) RA and B was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and B were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.
类风湿关节炎（RA）是最常见的免疫介导性关节炎。抗瓜氨酸肽抗体（ACPA）对 RA 具有高度特异性，并通过商业 CCP2 检测进行检测。MHC 中 RA 的遗传驱动因素在 CCP2 阳性和阴性 RA 亚组中是不同的，特别是在 HLA-DRB1 中。然而，HLA-B 中氨基酸位置 9 的天门冬氨酸（B）增加了两个 RA 亚组的风险。在这里，我们探讨了与 RA 相关的个体血清学如何驱动 MHC 内的关联。为了定义与 RA 相关的特定 ACPA 血清学的 MHC 差异，我们在来自四个队列的受 RA 影响的病例受试者中（n=6805）共定量了 19 种不同的 ACPA。我们发现一组紧密共现的抗体（经典血清学，包含 CCP2），以及几种独立表达的抗体（非经典血清学）。在将 HLA 变体导入 6805 例病例受试者和 13467 例对照受试者后，我们根据经典和/或非经典血清学的存在，基于 RA 亚组测试了 HLA 区域与 RA 之间的关联。我们分别检查了 CCP2(+)和 CCP2(-)RA 病例受试者。在 CCP2(-)RA 中，我们观察到 CCP2(-)RA 与 B 之间的关联来自于非经典血清学阳性的个体（总体_p=9.2×10）。同样，在 CCP2(+)RA 中，我们观察到 CCP2(+)RA 亚组与 B 之间的关联与阳性经典血清学的数量呈负相关（p=0.0096）。这些发现表明，精细特异性 ACPA 具有独特的遗传特征，这表明 RA 可能进一步细分，而不仅仅是血清阳性和血清阴性。
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