title: Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Center for Transgene Technology and Gene Therapy, KU Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Lambrechts
authors.forename: K
authors.initials: K
authors.lastname: Poesen
authors.forename: R
authors.initials: R
authors.lastname: Fernández-Santiago
authors.forename: A
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: R
authors.initials: R
authors.lastname: Del Bo
authors.forename: P W J
authors.initials: PW
authors.lastname: Van Vught
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.forename: S L
authors.initials: SL
authors.lastname: Marklund
authors.forename: A
authors.initials: A
authors.lastname: Brockington
authors.forename: I
authors.initials: I
authors.lastname: van Marion
authors.forename: J
authors.initials: J
authors.lastname: Anneser
authors.forename: C
authors.initials: C
authors.lastname: Shaw
authors.forename: A C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: N P
authors.initials: NP
authors.lastname: Leigh
authors.forename: G P
authors.initials: GP
authors.lastname: Comi
authors.forename: T
authors.initials: T
authors.lastname: Gasser
authors.forename: P J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: K E
authors.initials: KE
authors.lastname: Morrison
authors.forename: P M
authors.initials: PM
authors.lastname: Andersen
authors.forename: L H
authors.initials: LH
authors.lastname: Van den Berg
authors.forename: V
authors.initials: V
authors.lastname: Thijs
authors.forename: T
authors.initials: T
authors.lastname: Siddique
authors.forename: W
authors.initials: W
authors.lastname: Robberecht
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A