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Meta-analysis of VEGF variations in ALS: increased susceptibility in male carriers of the -2578AA genotype
  1. Diether Lambrechts (diether.lambrechts{at}med.kuleuven.be)
  1. CTG, Belgium
    1. Koen Poesen (koen.poesen{at}med.kuleuven.be)
    1. CTG, Belgium
      1. Peter Carmeliet
      1. CTG, Belgium
        1. Teepu Siddique (t-siddique{at}northwestern.edu)
        1. The Davee Department of Neurology and Clinical Neurosciences, United States
          1. Pamela J Shaw (pamela.shaw{at}sheffield.ac.uk)
          1. The Academic Neurology Unit, United Kingdom
            1. Alice Brockington (alicebrockington{at}yahoo.co.uk)
            1. The Academic Neurology Unit, Medical School, United Kingdom
              1. Nigel Leigh (pnigel.leigh{at}iop.kcl.ac.uk)
              1. Departments of Neurology and Medical and Molecular Genetics, United Kingdom
                1. Ammar Al-Chalabi (ammar.al-chalabi{at}iop.kcl.ac.uk)
                1. Departments of Neurology and Medical and Molecular Genetics, United Kingdom
                  1. Christopher Shaw (christopher.shaw{at}iop.kcl.ac.uk)
                  1. Departments of Neurology and Medical and Molecular Genetics, United Kingdom
                    1. Wim Robberecht (wim.robberecht{at}uz.kuleuven.ac.be)
                    1. Laboratory of Experimental Neurology, Belgium
                      1. Saeed Mahmood (drsaeed2k{at}yahoo.com)
                      1. The Davee Department of Neurology and Clinical Neurosciences, United States
                        1. P.W.J. Van Vught (p.w.j.vanvught{at}umcutrecht.nl)
                        1. The Davee Department of Neurology and Clinical Neurosciences, United States
                          1. Leonard H Van den Berg (lberg{at}umcutrecht.nl)
                          1. Department of Neurology, Netherlands
                            1. Peter Andersen (peter.andersen{at}neuro.umu.se)
                            1. Department of Neurology, Sweden
                              1. Roberto Del Bo (roberto.delbo{at}unimi.it)
                              1. The Dave Department of Neurology and Clinical Neurosciences, United States
                                1. Karen Morrison (k.morrison{at}bham.ac.uk)
                                1. k.morrison@bham.ac.uk, United Kingdom
                                  1. Rubén Fernández-Santiago (ruben.fernandez-santiago{at}uni-tuebingen.de)
                                  1. The Department of Neurodegenerative Diseases, Germany
                                    1. Vincent Thijs (vincent.thijs{at}uz.kuleuven.ac.be)
                                    1. Laboratory of Experimental Neurology, Belgium
                                      1. Thomas Gasser (thomas.gasser{at}uni-tuebingen.de)
                                      1. The Department of Neurodegenerative Diseases, Germany
                                        1. Johanna Anneser (johanna.anneser{at}med.uni-muenchen.de)
                                        1. Department of Neurology, Germany
                                          1. Albert Ludolph (albert.ludolph{at}rku.de)
                                          1. Department of Neurology, Germany
                                            1. Ingrid van Marion (ingrid.van_marion{at}med.lu.se)
                                            1. Department of Clinical Neurosciences, United Kingdom
                                              1. Stefan Marklund (stefan.marklund{at}medbio.umu.se)
                                              1. Department of Neurology, Sweden
                                                1. Giacomo Comi (giacomo.comi{at}unimi.it)
                                                1. Dino Ferrari Centre, Department of Neurological Sciences, Italy

                                                  Abstract

                                                  Background: Targeted delivery of the angiogenic factor, VEGF, to motor neurons prolongs survival in rodent models of ALS, while mice expressing reduced VEGF levels develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred an increased susceptibility to ALS in humans, but later studies challenged this initial finding.

                                                  Methods and Findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7,000 individuals from 8 European and 3 American populations were included in the analysis. Pooled odds ratios were calculated using fixed and random effect models and 4 potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analyses by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR=1.46 males versus females; CI=1.19-1.80; p=7.8 10E-5), even after correction for publication bias and multiple testing.

                                                  Conclusion: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with an increased susceptibility to ALS in male subjects reappraises the link between reduced VEGF levels and ALS, as originally revealed by the fortuitous mouse genetic studies.

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