Although genome‐wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1 , RGS1 , TIMMDC1 , HHEX , CXCR5 , LTBR , TSFM , GALC , TRAF3 , STAT3 , TNFSF14 , IFI30 , CD40 , and CYP24A1 ) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants‐enriched regions within CYP24A1 , FCRL1 , RGS1 , and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1 ) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1 , FCRL1 , and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon‐β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.

中文翻译：

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靶向重测序揭示了多发性硬化易感基因中罕见的变异富集。

尽管全基因组关联研究已经确定了许多与多发性硬化 (MS) 易感性相关的常见变异，但对罕见变异的相关性知之甚少。在这里，我们的目的是探讨在14个MS风险基因（罕见变异的作用FCRL1，RGS1，TIMMDC1，HHEX，CXCR5，LTBR，TSFM，GALC，TRAF3，STAT3，TNFSF14，IFI30，CD40和CYP24A1) 通过在 524 名 MS 病例和 546 名健康对照的伊比利亚人群中进行靶向重测序。CYP24A1、FCRL1、RGS1和TRAF3中的四个稀有变体富集区域被确定为与 MS 显着相关。功能研究显示，与非携带者相比，携带RGS1罕见变异的MS 患者外周血单核细胞中 G 蛋白信号传导 1 ( RGS1 ) 基因表达水平的调节剂显着降低，而未观察到CYP24A1、FCRL1和TRAF3基因表达的显着差异。罕见变异携带者和非携带者之间。免疫表型分析显示，相对于非携带者，患有RGS1罕见变异的MS 患者外周血 B 淋巴细胞中 RGS1 的表达显着降低。最后，与缺乏RGS1变异的MS 患者相比，来自携带RGS1罕见变异的MS 患者的外周血单核细胞显示，干扰素-β对RGS1基因表达的诱导显着降低。RGS1中稀有变异的存在强化了高遗传异质性的想法和稀有变异在 MS 发病机制中的作用。