Title: Meta-analysis of VEGF variations in ALS: increased susceptibility in male carriers of the -2578AA genotype
Authors: Lambrechts, Diether ×
Poesen, Koen
Fernández-Santiago, Rubén
Al-Chalabi, Ammar
Del Bo, Roberto
Van Vaught, Paul Wj
Khan, Saeed
Marklund, Stefan
Brockington, Alice
Van Marion, Ingrid
Anneser, Johanna
Shaw, Christopher
Ludolph, Albert
Leigh, Nigel
Comi, Giacomo
Gasser, Thomas
Shaw, Pamela J
Morrison, Karen
Andersen, Peter
Van den Berg, Leonard H
Thijs, Vincent
Siddique, Teepu
Robberecht, Wim
Carmeliet, Peter #
Issue Date: Dec-2009
Publisher: BMJ Publishing Group
Series Title: Journal of Medical Genetics vol:46 issue:12 pages:840-846
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.
ISSN: 0022-2593
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Vesalius Research Centre (-)
Molecular and Vascular Biology
Laboratory for Neurobiology (Vesalius Research Center)
Laboratory of Translational Genetics (Vesalius Research Center) (+)
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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