Joo Young Bin, Park Youngho, Kim Kwangwoo, Bang So-Young, Bae Sang-Cheol, Lee Hye-Soon
Department of Rheumatology, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea.
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
Int J Rheum Dis. 2018 Feb;21(2):440-446. doi: 10.1111/1756-185X.13090. Epub 2017 May 16.
Bone erosion is a major problem worsening quality of rheumatoid arthritis (RA) patients' lives. However, causal factors responsible for bone erosion in RA have remained unclear. We aimed to examine genetic variants conferring bone erosion in RA using a Korean genome-wide association study (GWAS) and to search for possible biological mechanisms underlying the development of bone erosion.
We obtained genome-wide single nucleotide polymorphism (SNP) data for 711 Korean RA patients using Illumina HapMap 550v3/660W arrays. Associations between SNPs and bone erosion status based on the Steinbrocker staging system were examined using multivariate logistic regression. Cell-type-specific enrichment of the epigenomic chromatin annotation H3K4me3 at the bone erosion associated variants was further investigated using National Institute of Health Roadmap Epigenomics data.
As we tested the associations between 439 289 SNPs and bone erosion in 385 patients with erosive RA and 326 with non-erosive RA, none of the tested SNPs reached the genome-wide significance threshold, although many loci showed modest genetic effect on bone erosion status with suggestive association (e.g., rs2741200 [P = 3.75 × 10 ] in the SLA-TG locus and rs12422918 [P = 4.13 × 10 ] in SRGAP1). However, the top-ranked SNPs and their linked proxies, which were mostly located in non-coding variants, were significantly co-localized with the highly tissue-specific regulatory marker H3K4me3 in CD8 memory T-cells (P = 0.014).
Although, there was no large-effect variants associated with bone erosion in our GWAS, we have shown that CD8 memory T-cells may have relevance with bone erosion in patients with RA through the analysis of ChiP-seq data.
骨侵蚀是一个严重影响类风湿关节炎（RA）患者生活质量的主要问题。然而，RA中导致骨侵蚀的因果因素仍不明确。我们旨在通过一项韩国全基因组关联研究（GWAS）来检测与RA骨侵蚀相关的基因变异，并寻找骨侵蚀发生发展的潜在生物学机制。
我们使用Illumina HapMap 550v3/660W芯片获取了711例韩国RA患者的全基因组单核苷酸多态性（SNP）数据。基于Steinbrocker分期系统，使用多变量逻辑回归分析SNP与骨侵蚀状态之间的关联。利用美国国立卫生研究院路线图表观基因组学数据，进一步研究骨侵蚀相关变异处表观基因组染色质注释H3K4me3的细胞类型特异性富集情况。
在对385例侵蚀性RA患者和326例非侵蚀性RA患者的439289个SNP与骨侵蚀的关联进行检测时，尽管许多位点对骨侵蚀状态显示出适度的遗传效应并具有提示性关联（例如，SLA-TG基因座中的rs2741200 [P = 3.75×10⁻⁵]和SRGAP1中的rs12422918 [P = 4.13×10⁻⁵]），但所检测的SNP均未达到全基因组显著性阈值。然而，排名靠前的SNP及其连锁代理（大多位于非编码变异中）与CD8记忆T细胞中高度组织特异性的调控标记H3K4me3显著共定位（P = 0.014）。
尽管在我们的GWAS中未发现与骨侵蚀相关的大效应变异，但通过对ChIP-seq数据的分析，我们表明CD8记忆T细胞可能与RA患者的骨侵蚀有关。
