RT Journal Article
SR Electronic
T1 Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the −2578AA genotype
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 840
OP 846
DO 10.1136/jmg.2008.058222
VO 46
IS 12
A1 D Lambrechts
A1 K Poesen
A1 R Fernández-Santiago
A1 A Al-Chalabi
A1 R Del Bo
A1 P W J Van Vught
A1 S Khan
A1 S L Marklund
A1 A Brockington
A1 I van Marion
A1 J Anneser
A1 C Shaw
A1 A C Ludolph
A1 N P Leigh
A1 G P Comi
A1 T Gasser
A1 P J Shaw
A1 K E Morrison
A1 P M Andersen
A1 L H Van den Berg
A1 V Thijs
A1 T Siddique
A1 W Robberecht
A1 P Carmeliet
YR 2009
UL http://jmg.bmj.com/content/46/12/840.abstract
AB 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.