Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission.
Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission.
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基因与复发和缓解中的基因分型和表达谱的合伙性有关多发性硬化症发病机理。
DOI：
10.1186/1471-2350-9-17
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发表时间：
2008-03-19
影响因子：
--
通讯作者：
Booth, David R.
中科院分区：
文献类型：
--
作者：
Arthur, Ariel T.;Armati, Patricia J.;Bye, Chris;Heard, Robert N. S.;Stewart, Graeme J.;Pollard, John D.;Booth, David R.
多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。虽然MS的发病机制尚不清楚，但它被广泛认为是由针对髓鞘蛋白和/或其他少突胶质细胞表位的T淋巴细胞介导的自身免疫性疾病。在这项研究中，我们研究了基因表达谱的复发和缓解期的复发性横纹肌肉瘤患者的外周血细胞利用基因芯片技术。从基因组筛选或先前的转录组学研究中鉴定了与MS易感性相关的区域中编码的失调基因。检测两个基因的近端启动子区多态性与疾病和表达水平的相关性。在复发和缓解阶段，确定了不同的失调基因组，包括参与细胞凋亡和炎症的基因。这些失调基因中的三个先前在基因组筛选中与MS易感性有关：TGFβ1、CD 58和DBC 1。TGFβ1在近端启动子中有一个常见的SNP：-508 T>C（rs 1800469）。基因分型两个澳大利亚的三人组（共620个家庭）发现了一个趋势，过度传播的T等位基因在MS的女性（p < 0.13）。缓解期CD 58和DBC 1的上调分别与其促进调节性T细胞和减少细胞增殖的假定作用一致。第四个基因ALOX 5在MS中一直被发现过表达。在ALOX 5启动子中确认了两种常见的遗传变异：-557 T>C（rs 12762303）和在位置-147和-176之间的6 bp串联重复多态性（GGGCGG）;但没有发现传输失真的证据。这些基因的失调标记了它们的代谢途径，以便进一步研究潜在的治疗干预
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous trancriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFβ1, CD58 and DBC1. TGFβ1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putatve promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.
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影响因子：
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通讯作者：
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