PMID- 25356403
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20141030
LR  - 20181113
IS  - 2328-9503 (Print)
IS  - 2328-9503 (Electronic)
IS  - 2328-9503 (Linking)
VI  - 1
IP  - 5
DP  - 2014 May
TI  - VAV1 and BAFF, via NFkappaB pathway, are genetic risk factors for myasthenia gravis.
PG  - 329-39
LID - 10.1002/acn3.51 [doi]
AB  - 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-alpha), 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-alpha loci were observed. INTERPRETATION: 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 (NFkappaB), thus 
      implicating dysregulation of proinflammatory signaling in predisposition to EOMG.
FAU - Avidan, Nili
AU  - Avidan N
AD  - Pharmacogenetics and Translational Genetics Center, The Rappaport Faculty of 
      Medicine and Research Institute, Technion-Israel Institute of Technology Haifa, 
      Israel.
FAU - Le Panse, Rozen
AU  - Le Panse R
AD  - Research Unit (INSERM U974/CNRS UMR7215//UPMC UM76/AIM) - Institute of Myology 
      Pitie-Salpetriere Paris, France.
FAU - Harbo, Hanne F
AU  - Harbo HF
AD  - Department of Neurology, Oslo University Hospital Ulleval, Norway ; Institute of 
      Clinical Medicine, University of Oslo Oslo, Norway.
FAU - Bernasconi, Pia
AU  - Bernasconi P
AD  - Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, 
      Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
FAU - Poulas, Konstantinos
AU  - Poulas K
AD  - Department of Pharmacy, University of Patras Patras, Greece.
FAU - Ginzburg, Elizabeta
AU  - Ginzburg E
AD  - Pharmacogenetics and Translational Genetics Center, The Rappaport Faculty of 
      Medicine and Research Institute, Technion-Israel Institute of Technology Haifa, 
      Israel.
FAU - Cavalcante, Paola
AU  - Cavalcante P
AD  - Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, 
      Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
FAU - Colleoni, Lara
AU  - Colleoni L
AD  - Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, 
      Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
FAU - Baggi, Fulvio
AU  - Baggi F
AD  - Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, 
      Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
FAU - Antozzi, Carlo
AU  - Antozzi C
AD  - Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, 
      Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
FAU - Truffault, Frederique
AU  - Truffault F
AD  - Research Unit (INSERM U974/CNRS UMR7215//UPMC UM76/AIM) - Institute of Myology 
      Pitie-Salpetriere Paris, France.
FAU - Horn-Saban, Shirley
AU  - Horn-Saban S
AD  - Department of Biological Services, Weizmann Institute of Science Rehovot, Israel.
FAU - Poschel, Simone
AU  - Poschel S
AD  - Department of Neurology, Tubingen University Medical Center Tubingen, Germany ; 
      Neurologische Klinik, Universitatsklinikum Erlangen Erlangen, Germany.
FAU - Zagoriti, Zoi
AU  - Zagoriti Z
AD  - Department of Pharmacy, University of Patras Patras, Greece.
FAU - Maniaol, Angelina
AU  - Maniaol A
AD  - Department of Neurology, Oslo University Hospital Ulleval, Norway.
FAU - Lie, Benedicte A
AU  - Lie BA
AD  - Institute of Clinical Medicine, University of Oslo Oslo, Norway ; Department of 
      Medical Genetics, Oslo University Hospital Ulleval, Norway.
FAU - Bernard, Isabelle
AU  - Bernard I
AD  - INSERM, U1043 Toulouse, F-31300, France ; Centre National de la Recherche 
      Scientifique, U5282 Toulouse, F-31300, France.
FAU - Saoudi, Abdelhadi
AU  - Saoudi A
AD  - INSERM, U1043 Toulouse, F-31300, France ; Centre National de la Recherche 
      Scientifique, U5282 Toulouse, F-31300, France.
FAU - Illes, Zsolt
AU  - Illes Z
AD  - Department of Neurology, University of Pecs Pecs, Hungary ; Department of 
      Neurology, Odense University Hospital, University of Southern Denmark Odense, 
      Denmark.
FAU - Casasnovas Pons, Carlos
AU  - Casasnovas Pons C
AD  - Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat Barcelona, Spain.
FAU - Melms, Arthur
AU  - Melms A
AD  - Department of Neurology, Tubingen University Medical Center Tubingen, Germany ; 
      Neurologische Klinik, Universitatsklinikum Erlangen Erlangen, Germany.
FAU - Tzartos, Socrates
AU  - Tzartos S
AD  - Department of Pharmacy, University of Patras Patras, Greece ; Hellenic Pasteur 
      Institute Athens, Greece.
FAU - Willcox, Nicholas
AU  - Willcox N
AD  - Clinical Neurology, Weatherall Institute for Molecular Medicine, University of 
      Oxford Oxford, United Kingdom.
FAU - Kostera-Pruszczyk, Anna
AU  - Kostera-Pruszczyk A
AD  - Department of Neurology, Medical University of Warsaw Warsaw, Poland.
FAU - Tallaksen, Chantal
AU  - Tallaksen C
AD  - Department of Neurology, Oslo University Hospital Ulleval, Norway ; Institute of 
      Clinical Medicine, University of Oslo Oslo, Norway.
FAU - Mantegazza, Renato
AU  - Mantegazza R
AD  - Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, 
      Fondazione Istituto Neurologico Carlo Besta (INNCB) Milan, Italy.
FAU - Berrih-Aknin, Sonia
AU  - Berrih-Aknin S
AD  - Research Unit (INSERM U974/CNRS UMR7215//UPMC UM76/AIM) - Institute of Myology 
      Pitie-Salpetriere Paris, France.
FAU - Miller, Ariel
AU  - Miller A
AD  - Pharmacogenetics and Translational Genetics Center, The Rappaport Faculty of 
      Medicine and Research Institute, Technion-Israel Institute of Technology Haifa, 
      Israel ; Division of Neuroimmunology, Carmel Medical Center Haifa, Israel.
LA  - eng
PT  - Journal Article
DEP - 20140411
PL  - United States
TA  - Ann Clin Transl Neurol
JT  - Annals of clinical and translational neurology
JID - 101623278
PMC - PMC4184684
EDAT- 2014/10/31 06:00
MHDA- 2014/10/31 06:01
PMCR- 2014/04/11
CRDT- 2014/10/31 06:00
PHST- 2014/02/09 00:00 [received]
PHST- 2014/02/12 00:00 [accepted]
PHST- 2014/10/31 06:00 [entrez]
PHST- 2014/10/31 06:00 [pubmed]
PHST- 2014/10/31 06:01 [medline]
PHST- 2014/04/11 00:00 [pmc-release]
AID - 10.1002/acn3.51 [doi]
PST - ppublish
SO  - Ann Clin Transl Neurol. 2014 May;1(5):329-39. doi: 10.1002/acn3.51. Epub 2014 Apr 
      11.