Meta-analysis of VEGF variations in ALS: increased susceptibility in male carriers of the -2578AA genotype
Diether Lambrechts 1*, Koen Poesen 1, Rubén Fernández-Santiago 2, Ammar Al-Chalabi 3, Roberto Del Bo 4, Paul WJ Van Vaught 4, Saeed Khan 5, Stefan Marklund 6, Alice Brockington 7, Ingrid Van Marion 8, Johanna Anneser 9, Christopher Shaw 10, Albert Ludolph 11, Nigel Leigh 10, giacomo comi 12, Thomas Gasser 2, Pamela J Shaw 7, Karen Morrison 13, Peter Andersen 6, Leonard H Van den Berg 14, Vincent Thijs 15, Teepu Siddique 4, Wim Robberecht 15 and Peter Carmeliet 16
1 CTG, Belgium
2 Hertie-Institute for Clinical Brain Research, Germany
3 Guy's, King's and St. Thomas' School of Medicine and Institute of Psychiatry, United Kingdom
4 Northwestern University, United States
5 Feinberg School of Medicine, United States
6 Institute of Clinical Neuroscience and Medical Genetics, Sweden
7 University of Sheffield, United Kingdom
8 The Medical School, University of Birmingham, United Kingdom
9 Ludwig-Maximilians University, Germany
10 King's and St. Thomas' School of Medicine and Institute of Psychiatry, United Kingdom
11 University Hospital of Ulm, Germany
12 University of Milan; I.R.C.C.S. Foundation Ospedale Policlinico, Mangiagalli, Italy
13 University of Birmingham, United Kingdom
14 Rudolf Magnus Institute of Neuroscience, Netherlands
15 Laboratory of Experimental Neurology, Belgium
16 The Center for Transgene Technology and Gene Therapy, Belgium
* To whom correspondence should be addressed. E-mail: diether.lambrechts{at}med.kuleuven.be.
Accepted 31 March 2008
 | Abstract |
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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.
