St. Clare's Mercy Hospital, 154 LeMarchant Road, St. John's, Newfoundland, Canada.
J Rheumatol. 2011 May;38(5):797-801. doi: 10.3899/jrheum.100758. Epub 2011 Mar 1.
Rheumatoid arthritis (RA) is a complex autoimmune rheumatic disease that is strongly influenced by genetic factors. Numerous genes are convincingly associated with RA, including genes in tumor necrosis factor signaling (TNF) and the nuclear factor-κB pathway. To date, except for genes within the HLA region, no data exist regarding potential copy number variations (CNV) involving RA-associated genes. We set out to identify genes affected by CNV that are associated with RA at a genome-wide level.
Data from the Wellcome Trust Case Control Consortium (WTCCC) were used in our analyses. The initial WTCCC cohort genotyped 3004 controls and 1999 RA cases using the GeneChip 500k Mapping Array Set. We performed a comparative intensity analysis using the PennCNV algorithm, which uses a hidden Markov model to detect CNV. A total of 2271 controls and 1572 RA samples passed quality control criteria and were included for association analysis. Association analysis was performed in 2 phases: (1) to identify CNV that are < 1 Mb with a population frequency < 5%; and (2) to identify large CNV that are > 1 Mb. Fishers' exact test was performed to quantify significance of the CNV.
We observed that the genome-wide CNV burden is 2-fold higher in patients with RA compared with controls. We identified 11 rare copy number variable regions with < 5% frequency that had an association with RA that reached a p < 1 × 10(-4). These include TNFAIP3 and TNIP1, which has been implicated in association studies for RA, systemic lupus erythematosus, and psoriasis. We identified CNV involving IRF1, which functions as a transcription activator of genes induced by interferons; ALOX5AP and LCP2, involved in inflammatory mediation; B2M, an MHC-class I associated gene; and PRKCH, a gene involved in T cell signaling pathways. A 57 kb deletion with 1% frequency in RA cases at 7p21.3 was also observed. Six of these loci overlap with CNV catalogued in the Database of Genomic Variants.
This is the first study to identify non-HLA RA-associated CNV using genome-wide analyses. Validation and functional significance of these deletions/duplications in RA and other autoimmune diseases need to be further investigated.
类风湿关节炎（RA）是一种复杂的自身免疫性风湿病，强烈受遗传因素影响。许多基因与 RA 明显相关，包括肿瘤坏死因子信号（TNF）和核因子-κB 通路中的基因。迄今为止，除了 HLA 区域内的基因外，尚无关于与 RA 相关的基因的潜在拷贝数变异（CNV）的数据。我们着手确定与 RA 相关的受 CNV 影响的基因，并在全基因组水平上进行研究。
我们使用了来自 Wellcome Trust Case Control Consortium（WTCCC）的数据。WTCCC 的初始队列使用 GeneChip 500k Mapping Array Set 对 3004 名对照和 1999 名 RA 病例进行了基因分型。我们使用 PennCNV 算法进行了比较强度分析，该算法使用隐马尔可夫模型来检测 CNV。共有 2271 名对照和 1572 名 RA 样本通过质量控制标准，用于关联分析。关联分析分 2 个阶段进行：（1）鉴定人群频率<5%且<1Mb 的 CNV；（2）鉴定>1Mb 的大片段 CNV。使用 Fisher 精确检验来量化 CNV 的显著性。
我们观察到，与对照组相比，RA 患者的全基因组 CNV 负担高 2 倍。我们鉴定出了 11 个罕见的拷贝数可变区域，频率<5%，与 RA 相关，达到了 p<1×10(-4)。这些区域包括 TNFAIP3 和 TNIP1，它们已被牵连到 RA、系统性红斑狼疮和银屑病的关联研究中。我们鉴定出了涉及 IRF1 的 CNV，IRF1 是干扰素诱导基因的转录激活因子；ALOX5AP 和 LCP2，参与炎症介质；B2M，MHC Ⅰ类相关基因；以及 PRKCH，参与 T 细胞信号通路的基因。还观察到了 7p21.3 处 RA 病例中频率为 1%的 57kb 缺失。其中 6 个与基因组变异数据库中列出的 CNV 重叠。
这是第一项使用全基因组分析来鉴定非 HLA RA 相关 CNV 的研究。需要进一步研究这些缺失/重复在 RA 和其他自身免疫性疾病中的验证和功能意义。
