Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease-relevant mechanisms. Building on our recent work showing the association of clinical disease course with post-mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology-associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T-allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.

中文翻译：

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死后多发性硬化症病变病理学受单核苷酸多态性的影响。

在过去的几十年里，已经确定了几种常见的单核苷酸多态性 (SNP) 与多发性硬化症 (MS) 的临床结果相关，但这些 SNP 临床影响的致病机制尚不清楚。部分原因是基因型功能转化为疾病相关机制存在困难。基于我们最近的工作显示了临床病程与死后 MS 病变特征的关联，我们假设与临床病程相关的 SNP 也将与尸检组织中特定的 MS 病变特征相关。为了检验这一假设，对来自荷兰脑库多发性硬化症尸检队列的 179 名多发性硬化症脑捐献者进行了 102 个 SNP 的基因分型，这些 SNP 是根据其报告的与临床结果的关联或与在多发性硬化症病变中显示差异基因表达的基因的关联进行选择的。与 MS 临床严重程度相关的三个 SNP 显示基因型与活动性病变比例（rs2234978/FAS 和 rs11957313/KCNIP1）或混合活动性/非活动性病变比例（rs8056098/CLEC16A）之间存在显着相关性。与 MS 病理相关基因相关的三个 SNP 显示与活动性病变比例 (rs3130253/MOG)、皮质灰质病变发生率 (rs1064395/NCAN) 或髓鞘再生病变比例 (rs5742909/CTLA4) 显着相关。此外，rs2234978/FAS T等位基因携带者显示血管周围T细胞和病灶周围少突胶质细胞中FAS基因表达水平增加，这些细胞类型与多发性硬化症病变形成有关。因此，通过将多发性硬化症脑尸检组织的病理特征与遗传学相结合，我们现在开始将与多发性硬化症临床结果相关的基因型转化为参与多发性硬化症病变发病机制的机制。