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Research paper
Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis
  1. P H C Kremer1,
  2. B P C Koeleman2,
  3. G JE Rinkel1,
  4. F P Diekstra1,
  5. L H van den Berg1,
  6. J H Veldink1,
  7. C J M Klijn1,3
  1. 1Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Biomedical Genetics and Complex Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  3. 3Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
  1. Correspondence to Dr C J M Klijn, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, UMC Utrecht, Postbus 85500, Utrecht 3508 GA, The Netherlands; c.j.m.klijn{at}


Background Case–control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results.

Methods We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by χ2 testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3.

Results In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1β, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005).

Conclusions The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1β, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis.


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