Department of Neurology, University Hospital of Wales, Cardiff, UK.
Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK.
Ann Neurol. 2024 Mar;95(3):459-470. doi: 10.1002/ana.26831. Epub 2023 Dec 9.
Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329 ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management.
We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes.
We were unable to detect any association between rs10191329 and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329 . However, we were able to replicate the association of two suggestive SNVs (rs7289446 and rs868824 ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset.
Identification of rs10191329 and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.
目前已知 233 个遗传位点与多发性硬化症（MS）易感性相关。最近两项独立的关键严重程度全基因组关联研究发现了首个全基因组显著的单核苷酸变异（SNV；rs10191329）和其他几个与总体残疾结果相关的提示性位点。现在重要的是要了解这些发现是否会影响个体患者的管理。
我们评估了这些进展 SNV 是否与 1455 名 MS 患者的特征良好的前瞻性队列中的详细临床表型相关。我们使用逻辑回归、生存分析和倾向评分匹配来预测相关的长期临床结果。
我们未能检测到 rs10191329 与一系列临床相关结局（例如，扩展残疾状态量表里程碑的时间、年龄相关的 MS 严重程度评分、发病时或随后复发时的解剖定位、年化复发率）之间存在任何关联。此外，使用基因型的倾向评分匹配进行极值结果病例对照分析未发现疾病严重程度与 rs10191329 之间存在关联。然而，我们能够复制两个提示性 SNV（rs7289446 和 rs868824）与固定残疾发展之间的关联，尽管效应大小适中，以及 HLA-DRB1*1501 与发病年龄之间的关联。
鉴定 rs10191329 和其他提示性 SNV 对于理解与 MS 严重程度相关的病理生理过程具有重要意义。然而，目前不太可能在临床环境中单独进行基因分型来指导疾病管理。本研究表明了在神经退行性疾病中独立复制与疾病进展相关的全基因组关联研究的重要性。ANN NEUROL 2024；95:459-470.
