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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. Rubén Fernández-Santiago (ruben.fernandez-santiago{at}uni-tuebingen.de)
      1. Hertie-Institute for Clinical Brain Research, Germany
        1. Ammar Al-Chalabi (ammar.al-chalabi{at}iop.kcl.ac.uk)
        1. Guy's, King's and St. Thomas' School of Medicine and Institute of Psychiatry, United Kingdom
          1. Roberto Del Bo (roberto.delbo{at}unimi.it)
          1. Northwestern University, United States
            1. Paul WJ Van Vught (p.w.j.vanvught{at}umcutrecht.nl)
            1. Northwestern University, United States
              1. Saeed Khan (drsaeed2k{at}yahoo.com)
              1. Feinberg School of Medicine, United States
                1. Stefan Marklund (stefan.marklund{at}medbio.umu.se)
                1. Institute of Clinical Neuroscience and Medical Genetics, Sweden
                  1. Alice Brockington (alicebrockington{at}yahoo.co.uk)
                  1. University of Sheffield, United Kingdom
                    1. Ingrid Van Marion (ingrid.van_marion{at}med.lu.se)
                    1. The Medical School, University of Birmingham, United Kingdom
                      1. Johanna Anneser (johanna.anneser{at}med.uni-muenchen.de)
                      1. Ludwig-Maximilians University, Germany
                        1. Christopher Shaw (christopher.shaw{at}iop.kcl.ac.uk)
                        1. King's and St. Thomas' School of Medicine and Institute of Psychiatry, United Kingdom
                          1. Albert Ludolph (albert.ludolph{at}rku.de)
                          1. University Hospital of Ulm, Germany
                            1. Nigel Leigh (pnigel.leigh{at}iop.kcl.ac.uk)
                            1. King's and St. Thomas' School of Medicine and Institute of Psychiatry, United Kingdom
                              1. giacomo comi (giacomo.comi{at}unimi.it)
                              1. University of Milan; I.R.C.C.S. Foundation Ospedale Policlinico, Mangiagalli, Italy
                                1. Thomas Gasser (thomas.gasser{at}uni-tuebingen.de)
                                1. Hertie-Institute for Clinical Brain Research, Germany
                                  1. Pamela J Shaw (pamela.shaw{at}sheffield.ac.uk)
                                  1. University of Sheffield, United Kingdom
                                    1. Karen Morrison (k.morrison{at}bham.ac.uk)
                                    1. University of Birmingham, United Kingdom
                                      1. Peter Andersen (peter.andersen{at}neuro.umu.se)
                                      1. Institute of Clinical Neuroscience and Medical Genetics, Sweden
                                        1. Leonard H Van den Berg (lberg{at}umcutrecht.nl)
                                        1. Rudolf Magnus Institute of Neuroscience, Netherlands
                                          1. Vincent Thijs (vincent.thijs{at}uz.kuleuven.ac.be)
                                          1. Laboratory of Experimental Neurology, Belgium
                                            1. Teepu Siddique (t-siddique{at}northwestern.edu)
                                            1. Northwestern University, United States
                                              1. Wim Robberecht (wim.robberecht{at}uz.kuleuven.ac.be)
                                              1. Laboratory of Experimental Neurology, Belgium
                                                1. Peter Carmeliet (peter.carmeliet{at}med.kuleuven.be)
                                                1. The Center for Transgene Technology and Gene Therapy, Belgium

                                                  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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