Integrative Analyses for Functional Mechanisms Underlying Associations for Rheumatoid Arthritis
Integrative Analyses for Functional Mechanisms Underlying Associations for Rheumatoid Arthritis
复制标题
类风湿关节炎相关功能机制的综合分析
DOI：
10.3899/jrheum.121119
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发表时间：
2013-07-01
影响因子：
3.9
通讯作者：
Zhang, Zeng-Li
中科院分区：
文献类型：
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作者：
Deng, Fei-Yan;Lei, Shu-Feng;Zhang, Zeng-Li
Objective.广泛的关联分析，包括全基因组关联研究（GWAS）和强大的荟萃分析研究已经确定了一长串的基因座与类风湿关节炎（RA）在非常大的人群，但他们中的大多数建立的统计学关联的遗传标记和RA仅在DNA水平上，没有支持的证据功能相关性。我们的研究作为一项试验，通过搜索公开可用的数据集和结果来检测RA相关的功能机制。方法.基于公开的数据集和结果，我们进行了综合分析（跨牵连位点的基因关系分析，差异基因表达分析和功能注释聚类分析），并将其与表达数量性状位点（eQTL）结果相结合，以剖析RA相关性的功能机制。结果通过检索2个GWAS、Integrator和PheGenI，我们选择了98个RA关联结果（p < 10−5）。在这些关联中，我们发现8个单核苷酸多态性（SNP; rs 1600249、rs 2736340、rs3093023、rs3093024、rs 4810485、rs615672、rs660895和rs 9272219）作为相应eQTL基因的顺式效应调节子（非HLA区域中的BLK和CD 4; HLA区域中的CCR 6、HLA-DQA 1和HLA-DQB 1），其也在RA相关细胞组中差异表达。这5个基因在功能上与免疫应答密切相关。结论我们的研究结果揭示了8个SNP与相应基因相关的功能机制。这项研究是一个例子，挖掘公开可用的数据集，并导致验证显着的疾病相关结果。利用公共数据资源进行综合分析，可以深入了解人类疾病的分子遗传机制。
Objective. Extensive association analyses including genome-wide association studies (GWAS) and powerful metaanalysis studies have identified a long list of loci associated with rheumatoid arthritis (RA) in very large populations, but most of them established statistical associations of genetic markers and RA only at the DNA level, without supporting evidence of functional relevance. Our study serves as a trial to detect the functional mechanisms underlying associations for RA by searching publicly available datasets and results. Methods. Based on publicly available datasets and results, we performed integrative analyses (gene relationships across implicated loci analysis, differential gene expression analysis, and functional annotation clustering analysis) and combined them with the expression quantitative trait locus (eQTL) results to dissect functional mechanisms underlying the associations for RA. Results. By searching 2 GWAS, Integrator and PheGenI, we selected 98 RA association results (p < 10−5). Among these associations, we found that 8 single-nucleotide polymorphisms (SNP; rs1600249, rs2736340, rs3093023, rs3093024, rs4810485, rs615672, rs660895, and rs9272219) serve as cis-effect regulators of the corresponding eQTL genes (BLK and CD4 in non-HLA region; CCR6, HLA-DQA1, and HLA-DQB1 in HLA region) that also were differentially expressed in RA-related cell groups. These 5 genes are closely related with immune response in function. Conclusion. Our results showed the functional mechanisms underlying the associations of 8 SNP and the corresponding genes. This study is an example of mining publicly available datasets and results in validation of significant disease-association results. Using public data resources for integrative analyses may provide insights into the molecular genetic mechanisms underlying human diseases.