Pharmacogenetics and Translational Genetics Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology Haifa, Israel.
Research Unit (INSERM U974/CNRS UMR7215//UPMC UM76/AIM) - Institute of Myology Pitié-Salpêtrière Paris, France.
Ann Clin Transl Neurol. 2014 May;1(5):329-39. doi: 10.1002/acn3.51. Epub 2014 Apr 11.
To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy.
Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres.
ALLELE FREQUENCY DIFFERENCES WERE FOUND IN FOUR NOVEL LOCI: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA-DRA and TNF-α loci were observed.
The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG.
应用两阶段关联研究、探索和复制策略，确定易患早发性重症肌无力（EOMG）的新遗传位点。
由参与 MG 不同研究方面的小组的成员选择 34 个基因座和一个确认基因座，即人类白细胞抗原（HLA）-DRA，作为候选基因。在探索阶段，对 384 名 EOMG 和 384 名匹配对照者的这些候选基因进行了基因分型，发现 8 个基因中的等位基因频率存在显著差异。在复制阶段，对来自 9 个欧洲中心的 1177 名 EOMG 患者和 814 名对照者的 8 个候选基因和一个确认基因座进行了基因分型。
在四个新基因座中发现了等位基因频率差异：CD86、AKAP12、VAV1、B 细胞激活因子（BAFF）和肿瘤坏死因子-α（TNF-α），并且在所有 9 个队列中这些差异都是一致的。单倍型趋势检验支持病例与对照者之间等位基因频率的差异。此外，在 HLA-DRA 和 TNF-α 基因座中观察到女性与男性患者的等位基因频率差异。
HLA 复合物外的 EOMG 遗传关联是新颖的，并且具有重要意义，因为 VAV1 是 T 和 B 细胞激活所必需的关键信号转导物，而 BAFF 是一种在 B 细胞增殖和分化中发挥重要作用的细胞因子。此外，我们注意到易患 VAV1 和 BAFF 单倍型之间存在显著的上位性；它们结合在一起比单独存在时风险更大。这些，以及 CD86，共享相同的信号通路，即核因子-κB（NFκB），因此暗示了促炎信号的失调在 EOMG 的易感性中起作用。
