title: VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis.
abstract: OBJECTIVE
  To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmacogenetics and Translational Genetics Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology Haifa, Israel.
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authors.affiliation: Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
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authors.affiliation: Pharmacogenetics and Translational Genetics Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology Haifa, Israel.
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authors.affiliation: Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
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authors.affiliation: Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
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authors.affiliation: Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
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authors.affiliation: Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
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authors.affiliation: Research Unit (INSERM U974/CNRS UMR7215//UPMC UM76/AIM) - Institute of Myology Pitié-Salpêtrière Paris, France.
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authors.affiliation: INSERM, U1043 Toulouse, F-31300, France ; Centre National de la Recherche Scientifique, U5282 Toulouse, F-31300, France.
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authors.affiliation: Department of Neurology, Tübingen University Medical Center Tubingen, Germany ; Neurologische Klinik, Universitätsklinikum Erlangen Erlangen, Germany.
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authors.affiliation: Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
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authors.affiliation: Research Unit (INSERM U974/CNRS UMR7215//UPMC UM76/AIM) - Institute of Myology Pitié-Salpêtrière Paris, France.
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