Department of Neurology, MS Center ErasMS, Erasmus University Medical Center, Rotterdam, the Netherlands.
Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands.
Eur J Neurol. 2021 Nov;28(11):3731-3741. doi: 10.1111/ene.15019. Epub 2021 Jul 27.
Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population.
We included genotyped participants from the population-based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS-PRSs on total T cell numbers (n = 1261), CD4 and CD8 lineages, and subsets therein (n= 675). In addition, T-cell-specific PRSs were constructed based on functional pathway data.
The MS-PRS negatively correlated with CD8 T cell frequencies (p = 2.92 × 10 ), which resulted in a positive association with CD4 /CD8 T cell ratios (p = 8.27 × 10 ). These associations were mainly driven by two of 195 genome-wide significant MS risk variants: the main genetic risk variant for MS, HLA-DRB1*15:01 and an HLA-B risk variant. We observed no significant associations for the T-cell-specific PRSs.
Our results suggest that MS-associated genetic variants affect T cell composition during childhood in the general population.
多发性硬化症（MS）患者的 T 细胞功能和组成发生改变。MS 的常见遗传风险变体影响免疫系统中的蛋白质。目前尚不清楚 T 细胞组成在多大程度上受到 MS 的遗传风险因素的影响，以及这可能在疾病发生之前如何影响。在这里，我们旨在评估多发性硬化症多基因风险评分（PRS）是否与一般人群中大量儿童的 T 细胞组成改变相关。
我们纳入了基于人群的 Generation R 研究中的基因分型参与者，他们在 6 岁时进行了血液 T 细胞免疫表型分析。方差分析用于确定 MS-PRS 对总 T 细胞数量（n=1261）、CD4 和 CD8 谱系及其内部亚群（n=675）的影响。此外，还根据功能途径数据构建了 T 细胞特异性 PRS。
MS-PRS 与 CD8 T 细胞频率呈负相关（p=2.92×10），这导致 CD4/CD8 T 细胞比值呈正相关（p=8.27×10）。这些关联主要由 195 个全基因组显著 MS 风险变体中的两个驱动：MS 的主要遗传风险变体 HLA-DRB1*15:01 和 HLA-B 风险变体。我们没有观察到 T 细胞特异性 PRS 的显著关联。
我们的结果表明，与 MS 相关的遗传变异会影响一般人群中儿童时期的 T 细胞组成。
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