Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex.
Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex.
复制标题
探究染色体 16p13.13 在多发性硬化症易感性中的复杂作用：CIITA-CLEC16A-SOCS1 基因复合体中的独立遗传信号。
DOI：
10.1093/hmg/ddr250
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发表时间：
2011
影响因子：
3.5
通讯作者：
Pericak-Vance
中科院分区：
文献类型：
--
作者：
Zuvich,RebeccaL;Bush,WilliamS;McCauley,JacobL;Beecham,AshleyH;DeJager,PhilipL;InternationalMultipleSclerosisGeneticsConsortium;Ivinson,AdrianJ;Compston,Alastair;Hafler,DavidA;Hauser,StephenL;Sawcer,StephenJ;Pericak-Vance
多发性硬化症（MS）是一种中枢神经系统的神经退行性自身免疫性疾病，许多研究表明MS具有很强的遗传成分。鉴定MS相关基因的独立研究通常表明在物理上接近的基因组区域中存在多个信号，尽管通过它们的接近性，并不总是清楚这些数据是否表明冗余或真正独立的遗传信号。最近，使用Illumina Custom BeadChip对三个MS研究样本进行了平行基因分型。这些发现多个显着相关的单核苷酸多态性内的600 kb的延伸染色体16 p13。在这里，我们提出了一个详细的分析，在这个地区的变异，澄清这些信号的独立性。该地区的连锁不平衡模式和Logistic回归分析的协会表明，该地区可能窝藏三个独立的MS疾病位点。此外，我们检查了该区域的顺式表达QTL，组蛋白修饰和CCCTC结合因子（CTCF）结合数据。我们还使用来自淋巴母细胞系的全基因组表达阵列数据测试了来自该区域的基因的相关表达。其中三个基因在基因座间表现出表达相关性。此外，在GM 12878淋巴母细胞样细胞系中，这三个基因位于缺乏H3 K27甲基化的连续区域中，表明开放的染色质构型。该区域可能只对MS的风险很小;然而，对该区域的研究无疑将深入了解这些基因的功能机制。这些数据强调了进一步研究染色体16 p13在MS发病机制中的表达和功能的重要性。
Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system, and numerous studies have shown that MS has a strong genetic component. Independent studies to identify MS-associated genes have often indicated multiple signals in physically close genomic regions, although by their proximity it is not always clear if these data indicate redundant or truly independent genetic signals. Recently, three MS study samples were genotyped in parallel using an Illumina Custom BeadChip. These revealed multiple significantly associated single-nucleotide polymorphisms within a 600 kb stretch on chromosome 16p13. Here we present a detailed analysis of variants in this region that clarifies the independent nature of these signals. The linkage disequilibrium patterns in the region and logistic regression analysis of the associations suggest that this region likely harbors three independent MS disease loci. Further, we examinedcis-expression QTLs, histone modifications and CCCTC-binding factor (CTCF) binding data in the region. We also tested for correlated expression of the genes from the region using whole-genome expression array data from lymphoblastoid cell lines. Three of the genes show expression correlations across loci. Furthermore, in the GM12878 lymphoblastoid cell line, these three genes are in a continuous region devoid of H3K27 methylation, suggesting an open chromatin configuration. This region likely only contributes minimal risk to MS; however, investigation of this region will undoubtedly provide insight into the functional mechanisms of these genes. These data highlight the importance of taking a closer look at the expression and function of chromosome 16p13 in the pathogenesis of MS.