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Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the −2578AA genotype
  1. D Lambrechts1,2,
  2. K Poesen1,2,
  3. R Fernández-Santiago3,
  4. A Al-Chalabi4,
  5. R Del Bo5,
  6. P W J Van Vught6,
  7. S Khan7,
  8. S L Marklund8,
  9. A Brockington9,
  10. I van Marion10,
  11. J Anneser3,
  12. C Shaw4,
  13. A C Ludolph3,
  14. N P Leigh4,
  15. G P Comi5,
  16. T Gasser3,
  17. P J Shaw9,
  18. K E Morrison10,
  19. P M Andersen8,
  20. L H Van den Berg6,
  21. V Thijs11,
  22. T Siddique7,
  23. W Robberecht11,
  24. P Carmeliet1,2
  1. 1
    The Center for Transgene Technology and Gene Therapy, K.U.Leuven, Leuven, B-3000, Belgium
  2. 2
    Department of Transgene Technology and Gene Therapy, VIB, Leuven, B-3000, Belgium
  3. 3
    Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Eberhard-Karls University, Tuebingen, Germany
  4. 4
    Departments of Neurology and Medical and Molecular Genetics, Guy’s, King’s and St Thomas’ School of Medicine and Institute of Psychiatry, King’s College London, London, UK
  5. 5
    Dino Ferrari Centre, Department of Neurological Sciences, University of Milan and IRCCS Foundation Ospedale Policlinico, Mangiagalli and Regina Elena, Milan, Italy
  6. 6
    Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
  7. 7
    The Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  8. 8
    Department of Neurology, Umea University Hospital, and Institute of Clinical Neuroscience and Medical Genetics, Umea University, Sweden
  9. 9
    The Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK
  10. 10
    Department of Clinical Neurosciences, Division of Neuroscience, The Medical School, University of Birmingham, Birmingham, UK
  11. 11
    Laboratory of Experimental Neurology, Campus Gasthuisberg, Leuven B-3000, Belgium
  1. Correspondence to Dr P Carmeliet, Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium; Peter.Carmeliet{at}


Background: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations 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 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 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four 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 analysis by gender revealed, however, that the −2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing.

Conclusions: 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 increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

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  • Additional data, figures and tables are published online only at

  • Competing interests PC is named as an inventor on a patent application regarding the use of VEGF to treat amyotrophic lateral sclerosis. The Flanders Interuniversity Institute for Biotechnology (VIB) is one of the joint owners of this patent application, and the said patent application has been licensed to an outside company. Neither VIB nor any of the authors have equity stakes in the company. However, VIB and PC stand to eventually receive royalties.

  • Ethics approval Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.