GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis
GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis
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DOI：
10.1038/gene.2016.23
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发表时间：
2016-07-01
影响因子：
5
通讯作者：
Pericak-Vance, M. A.
中科院分区：
文献类型：
--
作者：
Hussman, J. P.;Beecham, A. H.;Pericak-Vance, M. A.
为了鉴定与多发性硬化（MS）风险相关的基因和生物学相关途径，将全基因组关联研究降噪方法（GWAS-NR）应用于MS基因分型数据。根据连锁不平衡区的显著性定义关联区域。候选基因的交叉引用的基础上审查目前的文献，注意分子功能和直接相互作用的蛋白质。使用注释、可视化和综合发现数据库生成补充注释和途径富集评分。由GWAS-NR优先的220个MS易感基因的候选集高度富集了参与细胞、淋巴细胞和白细胞活化的正调控相关的生物学途径的基因（P分别为6.1E-15、1.2E-14和5.0E-14）。新型候选基因包括NF-κ B信号传导的关键调节因子以及CD 4+辅助性T细胞1型（Th 1）和辅助性T细胞17型（Th 17）谱系。发现GWAS-NR优先考虑的MS候选基因的大子集在调节NF-κ B介导的促炎性Th 1/Th 17 T细胞谱系的诱导和浸润以及T调节细胞维持免疫耐受的易处理途径中相互作用。这种机制提供了一种生物学背景，可能将MS的临床观察结果与可能赋予易感性的潜在遗传背景联系起来。
To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on the significance of linkage disequilibrium blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery. The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P = 6.1E-15, 1.2E-14 and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-kappa B signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-kappa B-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.