VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis
Article first published online: 11 APR 2014
© 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
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Annals of Clinical and Translational Neurology
Volume 1, Issue 5, pages 329–339, May 2014
How to Cite
Avidan, N., Le Panse, R., Harbo, H. F., Bernasconi, P., Poulas, K., Ginzburg, E., Cavalcante, P., Colleoni, L., Baggi, F., Antozzi, C., Truffault, F., Horn-Saban, S., Pöschel, S., Zagoriti, Z., Maniaol, A., Lie, B. A., Bernard, I., Saoudi, A., Illes, Z., Casasnovas Pons, C., Melms, A., Tzartos, S., Willcox, N., Kostera-Pruszczyk, A., Tallaksen, C., Mantegazza, R., Berrih-Aknin, S. and Miller, A. (2014), VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis. Annals of Clinical and Translational Neurology, 1: 329–339. doi: 10.1002/acn3.51
- Issue published online: 13 MAY 2014
- Article first published online: 11 APR 2014
- Manuscript Accepted: 12 FEB 2014
- Manuscript Received: 9 FEB 2014
- European Union. Grant Number: 242210
- Polish-Norwegian Research. Grant Number: PNRF-204-AI-1/07
- Sacta-Rashi Foundation
- U.K. Medical Research Council
- Association Française contre les Myopathies
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.