Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis
Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis
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DOI：
10.1007/s11033-012-1952-x
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发表时间：
2012-12-01
影响因子：
2.8
通讯作者：
Song, Gwan Gyu
中科院分区：
文献类型：
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作者：
Lee, Young Ho;Bae, Sang-Cheol;Song, Gwan Gyu
本研究旨在探讨系统性红斑狼疮（SLE）和类风湿性关节炎（RA）的单核苷酸多态性（SNPs）及其发病机制。本研究纳入了两个SLE全基因组关联研究（GWAS）数据集。使用1,527例SLE病例和3,421例欧洲血统对照中的737,984个SNP进行荟萃分析，并使用韩国RA GWAS数据集中满足p < 0.01阈值的4,429个SNP。将ICSNPathway（识别候选因果SNP和途径）分析应用于SLE GWAS数据集和RA GWAS数据集的荟萃分析结果。SLE GWAS荟萃分析的最显著结果涉及人类白细胞抗原（HLA）区域中的rs 2051549（p = 3.36 E-22）。在非HLA区域，荟萃分析确定了6个与SLE相关的具有全基因组意义的SNP（STAT 4、TNPO 3、BLK、FAM 167 A和IRF 5）。ICSNPathway确定了5个候选的因果SNP和13个候选的因果通路。这种基于途径的分析提供了三种有关生物学机制的假设。首先，rs 8084和rs7192 -> HLA-B->旁观者B细胞活化。第二，rs 1800629-> TNF ->细胞因子网络。第三，rs 1150752和rs 185819-> TNXB ->胶原代谢过程。ICSNPathway分析确定了三个候选的非HLA SNPs和四个候选的致病通路，涉及RA的PADI 4，MTR，PADI 2和TPH 2基因。我们确定了5个候选SNP和13条通路，涉及旁观者B细胞活化、细胞因子网络和胶原代谢加工，这些可能有助于SLE易感性，我们揭示了RA的候选致病非HLA SNP、基因和通路。
The aim of this study was to explore candidate single nucleotide polymorphisms (SNPs) and candidate mechanisms of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Two SLE genome-wide association studies (GWASs) datasets were included in this study. Meta-analysis was conducted using 737,984 SNPs in 1,527 SLE cases and 3,421 controls of European ancestry, and 4,429 SNPs that met a threshold of p < 0.01 in a Korean RA GWAS dataset was used. ICSNPathway (identify candidate causal SNPs and pathways) analysis was applied to the meta-analysis results of the SLE GWAS datasets, and a RA GWAS dataset. The most significant result of SLE GWAS meta-analysis concerned rs2051549 in the human leukocyte antigen (HLA) region (p = 3.36E-22). In the non-HLA region, meta-analysis identified 6 SNPs associated with SLE with genome-wide significance (STAT4, TNPO3, BLK, FAM167A, and IRF5). ICSNPathway identified five candidate causal SNPs and 13 candidate causal pathways. This pathway-based analysis provides three hypotheses of the biological mechanism involved. First, rs8084 and rs7192 -> HLA-DRA -> bystander B cell activation. Second, rs1800629 -> TNF -> cytokine network. Third, rs1150752 and rs185819 -> TNXB -> collagen metabolic process. ICSNPathway analysis identified three candidate causal non-HLA SNPs and four candidate causal pathways involving the PADI4, MTR, PADI2, and TPH2 genes of RA. We identified five candidate SNPs and thirteen pathways, involving bystander B cell activation, cytokine network, and collagen metabolic processing, which may contribute to SLE susceptibility, and we revealed candidate causal non-HLA SNPs, genes, and pathways of RA.